Neuroscience › Cellular and Molecular Neuroscience

Neuropeptides and Animal Physiology

Works Count: 102084

Wikipedia

Description

This cluster of papers explores the role of neuropeptides and their receptors in various physiological processes and disease states, including stress, anxiety, depression, immune modulation, and cardiovascular function. It covers a wide range of neuropeptides such as opioid receptors, calcitonin gene-related peptide, pituitary adenylate cyclase-activating polypeptide, and vasoactive intestinal peptide.

Keywords

Neuropeptides; Receptors; Opioid; Calcitonin Gene-Related Peptide; Pituitary Adenylate Cyclase-Activating Polypeptide; Stress; Anxiety; Depression; Immune Modulation; Vasoactive Intestinal Peptide

The Isolation of a New Hypotensive Peptide, Neurotensin, from Bovine Hypothalami

1973-10-01

Robert E. Carraway , Susan E. Leeman

Abstract A hypotensive peptide, designated neurotensin, has been discovered and isolated in pure form from acid-acetone extracts of bovine hypothalami by column chromatography and paper electrophoresis. The results of amino … Abstract A hypotensive peptide, designated neurotensin, has been discovered and isolated in pure form from acid-acetone extracts of bovine hypothalami by column chromatography and paper electrophoresis. The results of amino acid analyses of material recovered after paper electrophoresis at pH 3.5, 6.5, and 8.9 and chromatographic analyses of the dansylated material indicate that the peptide isolated by this procedure is homogenous. Its amino acid composition and apparent molecular weight estimated by chromatography on Sephadex G-25 indicate that neurotensin is a tridecapeptide composed of Lys, Arg2, Asx, Glx2, Pro2, Ileu, Leu2, Tyr2. Neurotensin lacks a free NH2-terminus; however, it possesses a free COOH terminus which can be acted upon by carboxypeptidase A. Neurotensin induces hypotension in the rat and can stimulate the contraction of guinea pig ileum and rat uterus; however, it produces relaxation of the rat duodenum. These pharmacological properties classify it as a kinin, yet its chemical composition distinguishes it from any known peptide.

Chemotaxis Under Agarose: A New and Simple Method for Measuring Chemotaxis and Spontaneous Migration of Human Polymorphonuclear Leukocytes and Monocytes

1975-12-01

Robert D. Nelson , Paul G. Quie , Richard L. Simmons

A variety of methods have been devised for the study of spontaneous and directed cell migration. Among these, the membrane filter method introduced by Boyden in 1962, with its more … A variety of methods have been devised for the study of spontaneous and directed cell migration. Among these, the membrane filter method introduced by Boyden in 1962, with its more recent modifications, has become the technique of choice for studies of leukocyte migration in vitro. This method, however, cannot be applied without alteration to studies of chemotaxis and spontaneous migration of cells of different types. We describe in this report a new and simple method for studying human leukocyte chemotaxis, in vitro, which is based upon migration of cells under agarose gel. This method has application to both polymorphonuclear leukocytes and monocytes, permits measurement of both chemotaxis and spontaneous migration, requires fewer cells per test, and is rapid, simple, reproducible, and inexpensive to set up.

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G-protein-coupled receptor heterodimerization modulates receptor function

1999-06-01

Bryen A. Jordan , Lakshmi A. Devi

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Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus

1996-04-01

Masashi Nibuya , EJ Nestler , R. S. Duman

The present study demonstrates that chronic, but not acute, adminstration of several different classes of antidepressants, including serotonin- and norepinephrine-selective reuptake inhibitors, increases the expression of cAMP response element binding … The present study demonstrates that chronic, but not acute, adminstration of several different classes of antidepressants, including serotonin- and norepinephrine-selective reuptake inhibitors, increases the expression of cAMP response element binding protein (CREB) mRNA in rat hippocampus. In contrast, chronic administration of several nonantidepressant psychotropic drugs did not influence expression of CREB mRNA, demonstrating the pharmacological specificity of this effect. In situ hybridization analysis demonstrates that antidepressant administration increases expression of CREB mRNA in CA1 and CA3 pyramidal and dentate gyrus granule cell layers of the hippocampus. In addition, levels of CRE immunoreactivity and of CRE binding activity were increased by chronic antidepressant administration, which indicates that expression and function of CREB protein are increased along with its mRNA. Chronic administration of the phosphodiesterase (PDE) inhibitors rolipram or papaverine also increased expression of CREB mRNA in hippocampus, demonstrating a role for the cAMP cascade. Moreover, coadministration of rolipram with imipramine resulted in a more rapid induction of CREB than with either treatment alone. Increased expression and function of CREB suggest that specific target genes may be regulated by these treatments. We have found that levels of brain-derived neurotrophic factor (BDNF) and trkB mRNA are also increased by administration of antidepressants or PDE inhibitors. These findings indicate that upregulation of CREB is a common action of chronic antidepressant treatments that may lead to regulation of specific target genes, such as BDNF and trkB, and to the long-term effects of these treatments on brain function.

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Immunohistochemical evidence for the existence of adrenaline neurons in the rat brain

1974-02-01

T. Ho ̈kfelt , Kjell Fuxé , Menek Goldstein +1 more

Galanin — a novel biologically active peptide from porcine intestine

1983-11-28

Kazuhiko Tatemoto , Åke Rökaeus , Hans Jörnvall +2 more

The isolation of a novel biologically active peptide, designated galanin, is described. The peptide was discovered by the detection of its C‐terminal amide structure in porcine intestinal extract using a … The isolation of a novel biologically active peptide, designated galanin, is described. The peptide was discovered by the detection of its C‐terminal amide structure in porcine intestinal extract using a chemical method. It was found that galanin consists of 29 amino acids and the complete amino acid sequence is: contract smooth muscle preparations from the rat and to cause a mild and sustained hyperglycemia in dog.

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A potent and selective endogenous agonist for the µ-opiate receptor

1997-04-01

James E. Zadina , Laszlo Hackler , Lin-Jun Ge +1 more

Distribution of substance P-like immunoreactivity in the central nervous system of the rat—I. Cell bodies and nerve terminals

1978-10-01

Å. Ljungdahl , Tomas Hökfelt , Göran Nilsson

Differential signal transduction by five splice variants of the PACAP receptor

1993-09-01

Dietmar Spengler , Christian Waeber , C. Pantaloni +4 more

Opiate Receptor: Demonstration in Nervous Tissue

1973-03-09

Candace B. Pert , Solomon H. Snyder

Tritiated naloxone, a powerful opiate antagonist, specifically binds to an opiate receptor of mammalian brain and guinea pig intestine. Competition for the opiate receptor by various opiates and their antagonists … Tritiated naloxone, a powerful opiate antagonist, specifically binds to an opiate receptor of mammalian brain and guinea pig intestine. Competition for the opiate receptor by various opiates and their antagonists closely parallels their pharmacological potency. The opiate receptor is confined to nervous tissue.

Substance P as neurogenic mediator of antidromic vasodilation and neurogenic plasma extravasation

1979-01-01

Fred Lembeck , Peter Holzer

Isolation of a novel 38 residue-hypothalamic polypeptide which stimulates adenylate cyclase in pituitary cells

1989-10-01

Atsuro Miyata , Akira Arimura , Raymond R. Dahl +5 more

A cell-killing monoclonal antibody (anti-Fas) to a cell surface antigen co-downregulated with the receptor of tumor necrosis factor.

1989-05-01

Shin Yonehara , A Ishii , M Yonehara

We have prepared an mAb specific for a human cell surface component (termed anti-Fas mAb). Anti-Fas shows cell-killing activity that is indistinguishable from the cytolytic activity of TNF. Fas antigen … We have prepared an mAb specific for a human cell surface component (termed anti-Fas mAb). Anti-Fas shows cell-killing activity that is indistinguishable from the cytolytic activity of TNF. Fas antigen was characterized by western blotting, indicating that Fas antigen is a cell surface protein with a molecular weight of 200,000, which is different from the molecular weight of TNF-R. Fas antigen, however, is co-downregulated with the TNF-R when cells sensitive to the cytolytic activity of TNF are incubated with either TNF or anti-Fas. In contrast, Fas antigen on cells insensitive to TNF is not co-downregulated with the TNF-R. We suggest that the cell-killing activity of TNF is mediated by Fas antigen associated with the TNF-R.

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Human tumour necrosis factor: precursor structure, expression and homology to lymphotoxin

1984-12-01

Diane Pennica , Glenn E. Nedwin , Joel S. Hayflick +6 more

Cholecystokinin decreases food intake in rats.

1973-01-01

James Gibbs , Robert C. Young , Gerard P. Smith

Immunohistochemical identification of neurons in the paraventricular nucleus of the hypothalamus that project to the medulla or to the spinal cord in the rat

1982-03-01

Paul E. Sawchenko , Larry W. Swanson

Abstract A method that allows the concurrent localization of an antigen and a retrogradely transported fluorescent dye (true blue) was used to identify, immunohistochemically, cells in the paraventricular nucleus of … Abstract A method that allows the concurrent localization of an antigen and a retrogradely transported fluorescent dye (true blue) was used to identify, immunohistochemically, cells in the paraventricular nucleus of the hypothalamus (PVH) that project to autonomic centers in the brainstem or in the spinal cord of the adult albino rat. After placing injections of true blue in the dorsal vagal complex or in upper thoracic segments of the spinal cord, series of evenly spaced sections through the PVH were stained with antisera directed against oxytocin, vasopressin, somatostatin, methionine‐enkephalin, or leucine‐encephalin. The results indicate that both oxytocin‐ and vasopressin‐stained cells in the PVH project to the spinal cord and (or) to the dorsal vagal complex, although about three times as many oxytocinstained cells were doubly labeled after injections centered in either terminal field. The oxytocin‐ and vasopressin‐stained cells that give rise to these long descending projections were found primarily in caudal parts of the parvo cellular division of the PVH, where immunoreactive cells were shown to be significantly smaller than oxytocin‐ and vasopressin‐stained cells in parts of the nucleus that project to the posterior pituitary. Small populations of cells in the PVH that cross‐react with antisera against somatostatin, leucine‐enkephalin, or methionine‐enkephalin were also shown to project directly to the region of the dorsal vagal complex and to the spinal cord, and to have a unique distribution within the PVH. Collectively, the total number of doubly labeled cells that were identified in these experiments accounts for only about one‐fourth of the total number of PVH neurons with long descending projections, thus suggesting that additional neuroactive substances are contained within these pathways.

Neuropeptide Y (NPY)‐like immunoreactivity in peripheral noradrenergic neurons and effects of NPY on sympathetic function

1982-12-01

Jan M. Lundberg , Lars Terenius , Tomas Hökfelt +6 more

Identification of two related pentapeptides from the brain with potent opiate agonist activity

1975-12-01

Joel W. Hughes , Terry Smith , H. W. Kosterlitz +3 more

Dynorphin Is a Specific Endogenous Ligand of the κ Opioid Receptor

1982-01-22

Charles Chavkin , Iain F. James , Avram Goldstein

In the guinea pig ileum myenteric plexus—longitudinal muscle preparation, dynorphin-(1—13) and the prototypical κ agonist ethylketocyclazocine had equally poor sensitivity to naloxone antagonism and showed selective cross protection in receptor … In the guinea pig ileum myenteric plexus—longitudinal muscle preparation, dynorphin-(1—13) and the prototypical κ agonist ethylketocyclazocine had equally poor sensitivity to naloxone antagonism and showed selective cross protection in receptor inactivation experiments with the alkylating antagonist β-chlornaltrexamine. In binding assays with membranes from guinea pig brain, ethylketocyclazocine and dynorphin-(1—13) amide were more potent in displacing tritium-labeled ethylketocyclazocine than in displacing typical μ and δ opioid receptor ligands. In the two preparations studied, the dynorphin receptor appears to be the same as the κ opioid receptor.

Anatomy of CNS opioid receptors

1988-01-01

Alfred Mansour , Henry Khachaturian , Michael E. Lewis +2 more

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Orphanin FQ: A Neuropeptide That Activates an Opioidlike G Protein-Coupled Receptor

1995-11-03

Rainer K. Reinscheid , Hans‐Peter Nothacker , Anne Bourson +7 more

A heptadecapeptide was identified and purified from porcine brain tissue as a ligand for an orphan heterotrimeric GTP- binding protein (G protein)- coupled receptor (LC132) that is similar in sequence … A heptadecapeptide was identified and purified from porcine brain tissue as a ligand for an orphan heterotrimeric GTP- binding protein (G protein)- coupled receptor (LC132) that is similar in sequence to opioid receptors. This peptide, orphanin FQ, has a primary structure reminiscent of that of opioid peptides. Nanomolar concentrations of orphanin FQ inhibited forskolin-stimulated adenylyl cyclase activity in cells transfected with LC132. This inhibitory activity was not affected by the addition of opioid ligands, nor did the peptide activate opioid receptors. Orphanin FQ bound to its receptor in a saturable manner and with high affinity. When injected intracerebroventricularly into mice, orphanin FQ caused a decrease in locomotor activity but did not induce analgesia in the hot-plate test. However, the peptide produced hyperalgesia in the tail-flick assay. Thus, orphanin FQ may act as a transmitter in the brain by modulating nociceptive and locomotor behavior.

Secretory products of macrophages.

1987-02-01

Carl Nathan

Numbers refer to selected reports of the indicated action.t NO, reportedly not observed.§ -, No observations reported, to my knowledge.11 ROI, reactive oxygen intermediates.'ADCC, antibody-dependent, cell-mediated cytotoxicity. Numbers refer to selected reports of the indicated action.t NO, reportedly not observed.§ -, No observations reported, to my knowledge.11 ROI, reactive oxygen intermediates.'ADCC, antibody-dependent, cell-mediated cytotoxicity.

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Bombesin-like peptides can function as autocrine growth factors in human small-cell lung cancer

1985-08-01

Frank Cuttitta , Desmond N. Carney , James L. Mulshine +4 more

Production of a novel neuropeptide encoded by the calcitonin gene via tissue-specific RNA processing

1983-07-01

Michael G. Rosenfeld , Jean‐Jacques Mermod , Susan Amara +5 more

Common precursor to corticotropins and endorphins

1977-07-01

Richard E. Mains , Betty Eipper , Nicholas Ling

Double-antibody immunoprecipitation procedures with antisera to endorphins and to corticotropin (ACTH) were used to study the biosynthesis of these peptides in a mouse pituitary tumor cell line. Cultures were incubated … Double-antibody immunoprecipitation procedures with antisera to endorphins and to corticotropin (ACTH) were used to study the biosynthesis of these peptides in a mouse pituitary tumor cell line. Cultures were incubated with a 3 H-labeled amino acid, and aliquots of culture medium were immunoprecipitated. Sodium dodecyl sulfate/polyacrylamide gel electrophoresis of [ 3 H]phenylalanine-labeled immunoprecipitates prepared with endorphin antisera resolved three forms of endorphin with apparent molecular weights of 31,000, 11,700, and 3500; immunoprecipitates prepared with the ACTH antiserum contained four forms of ACTH with apparent molecular weights of 31,000, 23,000, 13,000 and <4500. Sequential immunoprecipitation of culture medium with the ACTH antiserum and then with the endorphin antiserum (or the reverse order) indicated that both antisera precipitated the same 31,000 dalton molecule. Purified pools of the different forms of ACTH and endorphin were prepared by immunoprecipitation and gel filtration. The tryptic peptides found in [ 3 H]phenylalanine- or [ 3 H]tryptophan-labeled 31,000 dalton ACTH were identical to the tryptic peptides found in digests of 31,000 dalton endorphin labeled with the same amino acid. A tryptic peptide similar to the lipotropin tryptic peptide [βLPH(61-69)] that contains the opiate-active methionine-enkephalin sequence could be identified in 31,000 dalton ACTH and in all the different forms of endorphin. Most of the peptide cleaved from 31,000 dalton ACTH when it is converted to 23,000 dalton ACTH could be precipitated by endorphin antisera; this 11,700 dalton endorphin molecule is similar to the pituitary hormone βLPH in size and structure. The 3500 dalton endorphin is similar to β-endorphin in size and structure. The culture medium from the AtT-20 mouse pituitary tumor cells contained approximately equimolar amounts of ACTH-related peptides and endorphin-related peptides.

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High serum procalcitonin concentrations in patients with sepsis and infection

1993-02-01

M. Assicot , Claude Bohuon , D Gendrel +3 more

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Cloning of a Delta Opioid Receptor by Functional Expression

1992-12-18

Christopher J. Evans , Duane E. Keith , Heather Morrison +2 more

Opiate drugs have potent analgesic and addictive properties. These drugs interact with receptors that also mediate the response to endogenous opioid peptide ligands. However, the receptors for opioids have eluded … Opiate drugs have potent analgesic and addictive properties. These drugs interact with receptors that also mediate the response to endogenous opioid peptide ligands. However, the receptors for opioids have eluded definitive molecular characterization. By transient expression in COS cells and screening with an iodinated analog of the opioid peptide enkephalin, a complementary DNA clone encoding a functional δ opioid receptor has been identified. The sequence shows homology to G protein-coupled receptors, in particular the receptors for somatostatin, angiotensin, and interleukin-8.

Tumor Necrosis Factor (TNF)

1985-11-08

Lloyd J. Old

DIRECT EVIDENCE FOR NEUROGENIC INFLAMMATION AND ITS PREVENTION BY DENERVATION AND BY PRETREATMENT WITH CAPSAICIN

1967-09-01

N. Jancsó , Aurelia Jancsó‐Gábor , Janós Szolcsányi

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THE ABDOMINAL CONSTRICTION RESPONSE AND ITS SUPPRESSION BY ANALGESIC DRUGS IN THE MOUSE

1968-02-01

H. O. J. COLLIER , L. C. Dinneen , Christine A. Johnson +1 more

After intraperitoneal injection of a noxious agent, the rat and the mouse show a response consisting of a wave of constriction and elongation passing caudally along the abdominal wall, sometimes … After intraperitoneal injection of a noxious agent, the rat and the mouse show a response consisting of a wave of constriction and elongation passing caudally along the abdominal wall, sometimes accompanied by twisting of the trunk and followed by exten- sion of the hind limbs (Vander Wende & Margolin, 1956;Siegmund, Cadmus & Lu, 1957).This response has been variously called " writhing" (Vander Wende & Margolin, 1956), " stretching" (Koster, Anderson & de Beer, 1959), " cramping " (Murray & Miller, 1960} and " squirming " (Whittle, 1964a).Because of the emotional implications of these terms, it was later called the " abdominal constriction response " (Collier, Hammond, Horwood- Barrett & Schneider, 1964).We describe here an examination of the ability of a number of substances, including some occurring in tissues and causing pain in man (Keele & Armstrong, 1964), to elicit abdominal constriction responses in mice.Vander Wende & Margolin (1956) and Siegmund et al. (1957) showed that codeine, morphine and pethidine, given subcutaneously, and procaine, given intraperitoneally, suppressed the abdominal constriction response.They concluded that the response was nociceptive and they used it as a basis for testing analgesic drugs.The antinociceptive tests developed from this work have the advantage that they are sensitive to antipyretic drugs (Siegmund et al.,

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Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the µ-opioid-receptor gene

1996-10-01

Hans W. D. Matthes , Rafaël Maldonado , Frédéric Simonin +7 more

Calcitonin gene-related peptide is a potent vasodilator

1985-01-01

Susan D. Brain , T.J. Williams , John R. Tippins +2 more

Neuropeptide Y—a novel brain peptide with structural similarities to peptide YY and pancreatic polypeptide

1982-04-01

Kazuhiko Tatemoto , Mats Carlquist , Viktor Mutt

Efferent connections of the parabrachial nucleus in the rat

1980-09-01

Clifford B. Saper , Arthur D. Loewy

Neurotrophic and Neurotoxic Effects of Amyloid β Protein: Reversal by Tachykinin Neuropeptides

1990-10-12

Bruce A. Yankner , Lawrence K. Duffy , Daniel A. Kirschner

The amyloid β protein is deposited in the brains of patients with Alzheimer's disease but its pathogenic role is unknown. In culture, the amyloid β protein was neurotrophic to undifferentiated … The amyloid β protein is deposited in the brains of patients with Alzheimer's disease but its pathogenic role is unknown. In culture, the amyloid β protein was neurotrophic to undifferentiated hippocampal neurons at low concentrations and neurotoxic to mature neurons at higher concentrations. In differentiated neurons, amyloid β protein caused dendritic and axonal retraction followed by neuronal death. A portion of the amyloid β protein (amino acids 25 to 35) mediated both the trophic and toxic effects and was homologous to the tachykinin neuropeptide family. The effects of the amyloid β protein were mimicked by tachykinin antagonists and completely reversed by specific tachykinin agonists. Thus, the amyloid β protein could function as a neurotrophic factor for differentiating neurons, but at high concentrations in mature neurons, as in Alzheimer's disease, could cause neuronal degeneration.

Methods for drug discovery: development of potent, selective, orally effective cholecystokinin antagonists

1988-12-01

B. Evans , Kenneth E. Rittle , Mark G. Bock +7 more

3-(Acylamino)-5-phenyl-2H-1,4-benzodiazepines, antagonists of the peptide hormone cholecystokinin (CCK), are described. Developed by reasoned modification of the known anxiolytic benzodiazepines, these compounds provide highly potent, orally effective ligands selective for peripheral … 3-(Acylamino)-5-phenyl-2H-1,4-benzodiazepines, antagonists of the peptide hormone cholecystokinin (CCK), are described. Developed by reasoned modification of the known anxiolytic benzodiazepines, these compounds provide highly potent, orally effective ligands selective for peripheral (CCK-A) receptors, with binding affinities approaching or equaling that of the natural ligand CCK-8. The distinction between CCK-A receptors on the one hand and CNS (CCK-B), gastrin, and central benzodiazepine receptors on the other is demonstrated by using the structure-activity profiles of the new compounds. Details of the binding of these agents to CCK-A receptors are examined, and the method of development of these compounds is discussed in terms of its relevance to the general problem of drug discovery.

Neuropeptide Y: complete amino acid sequence of the brain peptide.

1982-09-01

Kazuhiko Tatemoto

The amino acid sequence of neuropeptide Y, a 36-residue peptide recently isolated from porcine brain, has been determined by using high performance liquid chromatography for separation of its tryptic and … The amino acid sequence of neuropeptide Y, a 36-residue peptide recently isolated from porcine brain, has been determined by using high performance liquid chromatography for separation of its tryptic and chymotryptic fragments and subsequent sequence analysis of the isolated fragments by an improved dansyl Edman subtractive technique. The amino acid sequence of neuropeptide Y has been found to be: Tyr-Pro-Ser-Lys-Pro-Asp-Asn-Pro-Gly-Glu-Asp-Ala-Pro-Ala-Glu-Asp-Leu-Ala-Arg-Tyr -Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH2. Neuropeptide Y has a high degree of sequence homology with peptide YY (70%), the newly isolated porcine intestinal peptide, and pancreatic polypeptide (50%). It is therefore proposed that neuropeptide Y, peptide YY, and pancreatic polypeptide are members of a newly recognized peptide family.

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Neuropeptide Y Distribution in the Rat Brain

1983-08-26

Y.S. Allen , Thomas E. Adrian , J.M. Allen +4 more

A massive neuronal system was detected by immunocytochemistry and radioimmunoassay with antibodies to neuropeptide Y, the recently isolated peptide of the pancreatic polypeptide family. Immunoreactive cell bodies and fibers were … A massive neuronal system was detected by immunocytochemistry and radioimmunoassay with antibodies to neuropeptide Y, the recently isolated peptide of the pancreatic polypeptide family. Immunoreactive cell bodies and fibers were most prevalent in cortical, limbic, and hypothalamic regions. Neuropeptide Y was extracted in concentrations higher than those of any other peptide hitherto discovered in the mammalian brain. Column chromatography of brain extracts and double immunostaining experiments indicate that neuropeptide Y is the endogenous brain peptide responsible for immunostaining of pancreatic polypeptide-like immunoreactivity in the mammalian brain.

Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor

1995-10-12

Jean‐Claude Meunier , Catherine Mollereau , Lawrence Toll +7 more

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Endogenous opioid peptides: multiple agonists and receptors

1977-06-01

John A.H. Lord , Angela A. Waterfield , John Hughes +1 more

β-Endorphin and Adrenocorticotropin Are Selected Concomitantly by the Pituitary Gland

1977-09-30

Roger Guillemin , Therese Vargo , Jean Rossier +5 more

The opiate-like peptide β-endorphin and adrenocorticotropin are concomitantly secreted in increased amounts by the adenohypophysis in response to acute stress or long-term adrenalectomy as well as in vitro in response … The opiate-like peptide β-endorphin and adrenocorticotropin are concomitantly secreted in increased amounts by the adenohypophysis in response to acute stress or long-term adrenalectomy as well as in vitro in response to purified corticotropin releasing factor and other secretagogues. Conversely, administration of the synthetic glucocorticoid dexamethasone inhibits the secretion of both adrenocorticotropin and β-endorphin. Thus, both hormones possess common and identical regulatory mechanisms and there may be a functional role for circulating β-endorphin.

Adrenomedullin: A Novel Hypotensive Peptide Isolated from Human Pheochromocytoma

1993-04-01

Kenichiro Kitamura , Kenji Kangawa , Masashi Kawamoto +4 more

Local effector functions of capsaicin-sensitive sensory nerve endings: Involvement of tachykinins, calcitonin gene-related peptide and other neuropeptides

1988-03-01

Peter Holzer

NEUROPEPTIDE Y AND HUMAN PANCREATIC POLYPEPTIDE STIMULATE FEEDING BEHAVIOR IN RATS

1984-07-01

John T. Clark , Pushpa S. Kalra , William R. Crowley +1 more

Observations that a pancreatic polypeptide-like substance, possibly neuropeptide Y, is present in hypothalamic areas and may coexist with catecholamines prompted evaluation of its role in controlling feeding behavior. Intracerebroventricular administration … Observations that a pancreatic polypeptide-like substance, possibly neuropeptide Y, is present in hypothalamic areas and may coexist with catecholamines prompted evaluation of its role in controlling feeding behavior. Intracerebroventricular administration of 2 or 10 μg of human pancreatic polypeptide to ovariectomized rats pretreated with estradiol benzoate plus progesterone significantly increased the number of animals feeding, and total food intake in tests conducted during the light phase of the day. Administration of neuropeptide Y, 2 or 10 μg, induced feeding in all rats, and food intake was 3 times greater than that observed after human pancreatic polypeptide injection. These findings imply that neuropeptide Y, or a closely related pancreatic polypeptide-like neuropeptide, plays an important role in neural regulation of feeding behavior.

RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor

1998-05-01

Linda M. McLatchie , Neil J. Fraser , Martin J. Main +6 more

The Metastasis Suppressor Gene KiSS-1 Encodes Kisspeptins, the Natural Ligands of the Orphan G Protein-coupled Receptor GPR54

2001-09-01

Masato Kotani , Michel Detheux , Ann L. Vandenbogaerde +7 more

Natural peptides displaying agonist activity on the orphan G protein-coupled receptor GPR54 were isolated from human placenta. These 54-, 14,- and 13-amino acid peptides, with a common RF-amide C terminus, … Natural peptides displaying agonist activity on the orphan G protein-coupled receptor GPR54 were isolated from human placenta. These 54-, 14,- and 13-amino acid peptides, with a common RF-amide C terminus, derive from the product of KiSS-1, a metastasis suppressor gene for melanoma cells, and were therefore designated kisspeptins. They bound with low nanomolar affinities to rat and human GPR54 expressed in Chinese hamster ovary K1 cells and stimulated PIP(2) hydrolysis, Ca(2+) mobilization, arachidonic acid release, ERK1/2 and p38 MAP kinase phosphorylation, and stress fiber formation but inhibited cell proliferation. Human GPR54 was highly expressed in placenta, pituitary, pancreas, and spinal cord, suggesting a role in the regulation of endocrine function. Stimulation of oxytocin secretion after kisspeptin administration to rats confirmed this hypothesis.

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Opioid-receptor mRNA expression in the rat CNS: anatomical and functional implications

1995-01-01

Alfred Mansour , Charles A. Fox , Huda Akil +1 more

Hydrolysis of Biological Peptides by Human Angiotensin-converting Enzyme-related Carboxypeptidase

2002-04-01

Chad Vickers , Paul Hales , Virendar K. Kaushik +7 more

Human angiotensin-converting enzyme-related carboxypeptidase (ACE2) is a zinc metalloprotease whose closest homolog is angiotensin I-converting enzyme. To begin to elucidate the physiological role of ACE2, ACE2 was purified, and its … Human angiotensin-converting enzyme-related carboxypeptidase (ACE2) is a zinc metalloprotease whose closest homolog is angiotensin I-converting enzyme. To begin to elucidate the physiological role of ACE2, ACE2 was purified, and its catalytic activity was characterized. ACE2 proteolytic activity has a pH optimum of 6.5 and is enhanced by monovalent anions, which is consistent with the activity of ACE. ACE2 activity is increased ∼10-fold by Cl− and F− but is unaffected by Br−. ACE2 was screened for hydrolytic activity against a panel of 126 biological peptides, using liquid chromatography-mass spectrometry detection. Eleven of the peptides were hydrolyzed by ACE2, and in each case, the proteolytic activity resulted in removal of the C-terminal residue only. ACE2 hydrolyzes three of the peptides with high catalytic efficiency: angiotensin II (1.Donoghue M. Hsieh F. Baronas E. Godbout K. Gosselin M. Stagliano N. Donovan M. Woolf B. Robison K. Jeyaseelan R. Breitbart R.E. Acton S. Circ. Res. 2000; 87: 1-9Crossref PubMed Google Scholar, 2.Skeggs L.T. Kahn J.R. Shumway N.P. J. Exp. Med. 1956; 103: 295-299Crossref PubMed Scopus (748) Google Scholar, 3.Francis G.S. N. Engl. J. Med. 2000; 342: 201-202Crossref PubMed Scopus (80) Google Scholar, 4.Blais C.J. Marceau F. Rouleau J.-L. Adam A. Peptides (Elmsford). 2000; 21: 1903-1940Crossref PubMed Scopus (121) Google Scholar, 5.Fox A.J. Lalloo U.G. Belvisi M.G. Bernareggi M. Chung K.F. Nat. Med. 1996; 2: 814-817Crossref PubMed Scopus (257) Google Scholar, 6.Tipnis S.R. Hooper N.M. Hyde R. Karran E. Christie G. Turner A.J. J. Biol. Chem. 2000; 275: 33238-33243Abstract Full Text Full Text PDF PubMed Scopus (1745) Google Scholar, 7.Fernandez M. Liu X. Wouters M.A. Heyberger S. Husain A. J. Biol. Chem. 2001; 276: 4998-5004Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 8.Shapiro R. Holmquist B. Riordan J.F. Biochemistry. 1983; 22: 3850-3857Crossref PubMed Scopus (81) Google Scholar) (k cat/K m = 1.9 × 106m−1 s−1), apelin-13 (k cat/K m = 2.1 × 106m−1s−1), and dynorphin A 1–13 (k cat/K m = 3.1 × 106m−1 s−1). The ACE2 catalytic efficiency is 400-fold higher with angiotensin II (1.Donoghue M. Hsieh F. Baronas E. Godbout K. Gosselin M. Stagliano N. Donovan M. Woolf B. Robison K. Jeyaseelan R. Breitbart R.E. Acton S. Circ. Res. 2000; 87: 1-9Crossref PubMed Google Scholar, 2.Skeggs L.T. Kahn J.R. Shumway N.P. J. Exp. Med. 1956; 103: 295-299Crossref PubMed Scopus (748) Google Scholar, 3.Francis G.S. N. Engl. J. Med. 2000; 342: 201-202Crossref PubMed Scopus (80) Google Scholar, 4.Blais C.J. Marceau F. Rouleau J.-L. Adam A. Peptides (Elmsford). 2000; 21: 1903-1940Crossref PubMed Scopus (121) Google Scholar, 5.Fox A.J. Lalloo U.G. Belvisi M.G. Bernareggi M. Chung K.F. Nat. Med. 1996; 2: 814-817Crossref PubMed Scopus (257) Google Scholar, 6.Tipnis S.R. Hooper N.M. Hyde R. Karran E. Christie G. Turner A.J. J. Biol. Chem. 2000; 275: 33238-33243Abstract Full Text Full Text PDF PubMed Scopus (1745) Google Scholar, 7.Fernandez M. Liu X. Wouters M.A. Heyberger S. Husain A. J. Biol. Chem. 2001; 276: 4998-5004Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 8.Shapiro R. Holmquist B. Riordan J.F. Biochemistry. 1983; 22: 3850-3857Crossref PubMed Scopus (81) Google Scholar) as a substrate than with angiotensin I (1.Donoghue M. Hsieh F. Baronas E. Godbout K. Gosselin M. Stagliano N. Donovan M. Woolf B. Robison K. Jeyaseelan R. Breitbart R.E. Acton S. Circ. Res. 2000; 87: 1-9Crossref PubMed Google Scholar, 2.Skeggs L.T. Kahn J.R. Shumway N.P. J. Exp. Med. 1956; 103: 295-299Crossref PubMed Scopus (748) Google Scholar, 3.Francis G.S. N. Engl. J. Med. 2000; 342: 201-202Crossref PubMed Scopus (80) Google Scholar, 4.Blais C.J. Marceau F. Rouleau J.-L. Adam A. Peptides (Elmsford). 2000; 21: 1903-1940Crossref PubMed Scopus (121) Google Scholar, 5.Fox A.J. Lalloo U.G. Belvisi M.G. Bernareggi M. Chung K.F. Nat. Med. 1996; 2: 814-817Crossref PubMed Scopus (257) Google Scholar, 6.Tipnis S.R. Hooper N.M. Hyde R. Karran E. Christie G. Turner A.J. J. Biol. Chem. 2000; 275: 33238-33243Abstract Full Text Full Text PDF PubMed Scopus (1745) Google Scholar, 7.Fernandez M. Liu X. Wouters M.A. Heyberger S. Husain A. J. Biol. Chem. 2001; 276: 4998-5004Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 8.Shapiro R. Holmquist B. Riordan J.F. Biochemistry. 1983; 22: 3850-3857Crossref PubMed Scopus (81) Google Scholar, 9.Rovere C. Barbero P. Kitabgi P. J. Biol. Chem. 1996; 271: 11368-11375Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, 10.Bunning P. Riordan J.F. Biochemistry. 1983; 22: 110-116Crossref PubMed Scopus (99) Google Scholar). ACE2 also efficiently hydrolyzes des-Arg9-bradykinin (k cat/K m = 1.3 × 105m−1 s−1), but it does not hydrolyze bradykinin. An alignment of the ACE2 peptide substrates reveals a consensus sequence of: Pro-X (1–3 residues)-Pro-Hydrophobic, where hydrolysis occurs between proline and the hydrophobic amino acid. Human angiotensin-converting enzyme-related carboxypeptidase (ACE2) is a zinc metalloprotease whose closest homolog is angiotensin I-converting enzyme. To begin to elucidate the physiological role of ACE2, ACE2 was purified, and its catalytic activity was characterized. ACE2 proteolytic activity has a pH optimum of 6.5 and is enhanced by monovalent anions, which is consistent with the activity of ACE. ACE2 activity is increased ∼10-fold by Cl− and F− but is unaffected by Br−. ACE2 was screened for hydrolytic activity against a panel of 126 biological peptides, using liquid chromatography-mass spectrometry detection. Eleven of the peptides were hydrolyzed by ACE2, and in each case, the proteolytic activity resulted in removal of the C-terminal residue only. ACE2 hydrolyzes three of the peptides with high catalytic efficiency: angiotensin II (1.Donoghue M. Hsieh F. Baronas E. Godbout K. Gosselin M. Stagliano N. Donovan M. Woolf B. Robison K. Jeyaseelan R. Breitbart R.E. Acton S. Circ. Res. 2000; 87: 1-9Crossref PubMed Google Scholar, 2.Skeggs L.T. Kahn J.R. Shumway N.P. J. Exp. Med. 1956; 103: 295-299Crossref PubMed Scopus (748) Google Scholar, 3.Francis G.S. N. Engl. J. Med. 2000; 342: 201-202Crossref PubMed Scopus (80) Google Scholar, 4.Blais C.J. Marceau F. Rouleau J.-L. Adam A. Peptides (Elmsford). 2000; 21: 1903-1940Crossref PubMed Scopus (121) Google Scholar, 5.Fox A.J. Lalloo U.G. Belvisi M.G. Bernareggi M. Chung K.F. Nat. Med. 1996; 2: 814-817Crossref PubMed Scopus (257) Google Scholar, 6.Tipnis S.R. Hooper N.M. Hyde R. Karran E. Christie G. Turner A.J. J. Biol. Chem. 2000; 275: 33238-33243Abstract Full Text Full Text PDF PubMed Scopus (1745) Google Scholar, 7.Fernandez M. Liu X. Wouters M.A. Heyberger S. Husain A. J. Biol. Chem. 2001; 276: 4998-5004Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 8.Shapiro R. Holmquist B. Riordan J.F. Biochemistry. 1983; 22: 3850-3857Crossref PubMed Scopus (81) Google Scholar) (k cat/K m = 1.9 × 106m−1 s−1), apelin-13 (k cat/K m = 2.1 × 106m−1s−1), and dynorphin A 1–13 (k cat/K m = 3.1 × 106m−1 s−1). The ACE2 catalytic efficiency is 400-fold higher with angiotensin II (1.Donoghue M. Hsieh F. Baronas E. Godbout K. Gosselin M. Stagliano N. Donovan M. Woolf B. Robison K. Jeyaseelan R. Breitbart R.E. Acton S. Circ. Res. 2000; 87: 1-9Crossref PubMed Google Scholar, 2.Skeggs L.T. Kahn J.R. Shumway N.P. J. Exp. Med. 1956; 103: 295-299Crossref PubMed Scopus (748) Google Scholar, 3.Francis G.S. N. Engl. J. Med. 2000; 342: 201-202Crossref PubMed Scopus (80) Google Scholar, 4.Blais C.J. Marceau F. Rouleau J.-L. Adam A. Peptides (Elmsford). 2000; 21: 1903-1940Crossref PubMed Scopus (121) Google Scholar, 5.Fox A.J. Lalloo U.G. Belvisi M.G. Bernareggi M. Chung K.F. Nat. Med. 1996; 2: 814-817Crossref PubMed Scopus (257) Google Scholar, 6.Tipnis S.R. Hooper N.M. Hyde R. Karran E. Christie G. Turner A.J. J. Biol. Chem. 2000; 275: 33238-33243Abstract Full Text Full Text PDF PubMed Scopus (1745) Google Scholar, 7.Fernandez M. Liu X. Wouters M.A. Heyberger S. Husain A. J. Biol. Chem. 2001; 276: 4998-5004Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 8.Shapiro R. Holmquist B. Riordan J.F. Biochemistry. 1983; 22: 3850-3857Crossref PubMed Scopus (81) Google Scholar) as a substrate than with angiotensin I (1.Donoghue M. Hsieh F. Baronas E. Godbout K. Gosselin M. Stagliano N. Donovan M. Woolf B. Robison K. Jeyaseelan R. Breitbart R.E. Acton S. Circ. Res. 2000; 87: 1-9Crossref PubMed Google Scholar, 2.Skeggs L.T. Kahn J.R. Shumway N.P. J. Exp. Med. 1956; 103: 295-299Crossref PubMed Scopus (748) Google Scholar, 3.Francis G.S. N. Engl. J. Med. 2000; 342: 201-202Crossref PubMed Scopus (80) Google Scholar, 4.Blais C.J. Marceau F. Rouleau J.-L. Adam A. Peptides (Elmsford). 2000; 21: 1903-1940Crossref PubMed Scopus (121) Google Scholar, 5.Fox A.J. Lalloo U.G. Belvisi M.G. Bernareggi M. Chung K.F. Nat. Med. 1996; 2: 814-817Crossref PubMed Scopus (257) Google Scholar, 6.Tipnis S.R. Hooper N.M. Hyde R. Karran E. Christie G. Turner A.J. J. Biol. Chem. 2000; 275: 33238-33243Abstract Full Text Full Text PDF PubMed Scopus (1745) Google Scholar, 7.Fernandez M. Liu X. Wouters M.A. Heyberger S. Husain A. J. Biol. Chem. 2001; 276: 4998-5004Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 8.Shapiro R. Holmquist B. Riordan J.F. Biochemistry. 1983; 22: 3850-3857Crossref PubMed Scopus (81) Google Scholar, 9.Rovere C. Barbero P. Kitabgi P. J. Biol. Chem. 1996; 271: 11368-11375Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, 10.Bunning P. Riordan J.F. Biochemistry. 1983; 22: 110-116Crossref PubMed Scopus (99) Google Scholar). ACE2 also efficiently hydrolyzes des-Arg9-bradykinin (k cat/K m = 1.3 × 105m−1 s−1), but it does not hydrolyze bradykinin. An alignment of the ACE2 peptide substrates reveals a consensus sequence of: Pro-X (1–3 residues)-Pro-Hydrophobic, where hydrolysis occurs between proline and the hydrophobic amino acid. Human angiotensin-converting enzyme-related carboxypeptidase (ACE2) 1The abbreviations used are: ACE2angiotensin-converting enzyme-related carboxypeptidaseACEangiotensin I-converting enzymeAng Iangiotensin I (1.Donoghue M. Hsieh F. Baronas E. Godbout K. Gosselin M. Stagliano N. Donovan M. Woolf B. Robison K. Jeyaseelan R. Breitbart R.E. Acton S. Circ. Res. 2000; 87: 1-9Crossref PubMed Google Scholar, 2.Skeggs L.T. Kahn J.R. Shumway N.P. J. Exp. Med. 1956; 103: 295-299Crossref PubMed Scopus (748) Google Scholar, 3.Francis G.S. N. Engl. J. Med. 2000; 342: 201-202Crossref PubMed Scopus (80) Google Scholar, 4.Blais C.J. Marceau F. Rouleau J.-L. Adam A. Peptides (Elmsford). 2000; 21: 1903-1940Crossref PubMed Scopus (121) Google Scholar, 5.Fox A.J. Lalloo U.G. Belvisi M.G. Bernareggi M. Chung K.F. Nat. Med. 1996; 2: 814-817Crossref PubMed Scopus (257) Google Scholar, 6.Tipnis S.R. Hooper N.M. Hyde R. Karran E. Christie G. Turner A.J. J. Biol. Chem. 2000; 275: 33238-33243Abstract Full Text Full Text PDF PubMed Scopus (1745) Google Scholar, 7.Fernandez M. Liu X. Wouters M.A. Heyberger S. Husain A. J. Biol. Chem. 2001; 276: 4998-5004Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 8.Shapiro R. Holmquist B. Riordan J.F. Biochemistry. 1983; 22: 3850-3857Crossref PubMed Scopus (81) Google Scholar, 9.Rovere C. Barbero P. Kitabgi P. J. Biol. Chem. 1996; 271: 11368-11375Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, 10.Bunning P. Riordan J.F. Biochemistry. 1983; 22: 110-116Crossref PubMed Scopus (99) Google Scholar)Ang IIangiotensin II (1.Donoghue M. Hsieh F. Baronas E. Godbout K. Gosselin M. Stagliano N. Donovan M. Woolf B. Robison K. Jeyaseelan R. Breitbart R.E. Acton S. Circ. Res. 2000; 87: 1-9Crossref PubMed Google Scholar, 2.Skeggs L.T. Kahn J.R. Shumway N.P. J. Exp. Med. 1956; 103: 295-299Crossref PubMed Scopus (748) Google Scholar, 3.Francis G.S. N. Engl. J. Med. 2000; 342: 201-202Crossref PubMed Scopus (80) Google Scholar, 4.Blais C.J. Marceau F. Rouleau J.-L. Adam A. Peptides (Elmsford). 2000; 21: 1903-1940Crossref PubMed Scopus (121) Google Scholar, 5.Fox A.J. Lalloo U.G. Belvisi M.G. Bernareggi M. Chung K.F. Nat. Med. 1996; 2: 814-817Crossref PubMed Scopus (257) Google Scholar, 6.Tipnis S.R. Hooper N.M. Hyde R. Karran E. Christie G. Turner A.J. J. Biol. Chem. 2000; 275: 33238-33243Abstract Full Text Full Text PDF PubMed Scopus (1745) Google Scholar, 7.Fernandez M. Liu X. Wouters M.A. Heyberger S. Husain A. J. Biol. Chem. 2001; 276: 4998-5004Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 8.Shapiro R. Holmquist B. Riordan J.F. Biochemistry. 1983; 22: 3850-3857Crossref PubMed Scopus (81) Google Scholar)Mca-APK(Dnp)((7-methoxycoumarin-4-yl)acetyl-Ala-Pro-Lys(2,4-dinitrophenyl)-OH)Mca-YVADAPK(Dnp)(7-methoxycoumarin-4-yl)acetyl-Tyr-Val-Ala-Asp-Ala-Pro-Lys(2,4-dinitrophenyl)-OHMALDI-TOFmatrix-assisted laser desorption ionization time-of-flightHPLChigh pressure liquid chromatographyMES4-morpholineethanesulfonic acidCHES2- (cyclohexylamino)ethanesulfonic acidCAPS3-(cyclohexylamino) propanesulfonic acidbis-Tris propane1,3-bis[tris(hydroxymethyl)methylamino]propane is a close homolog of human endothelial angiotensin I-converting enzyme (ACE, EC 3.4.15.1), with 42% protein sequence identity between the catalytic domains (for sequence alignment, see Ref. 1.Donoghue M. Hsieh F. Baronas E. Godbout K. Gosselin M. Stagliano N. Donovan M. Woolf B. Robison K. Jeyaseelan R. Breitbart R.E. Acton S. Circ. Res. 2000; 87: 1-9Crossref PubMed Google Scholar). ACE, a component of the renin-angiotensin system, is a zinc metalloprotease that catalyzes cleavage of the C-terminal dipeptide from Ang I to produce the potent vasopressor octapeptide Ang II (2.Skeggs L.T. Kahn J.R. Shumway N.P. J. Exp. Med. 1956; 103: 295-299Crossref PubMed Scopus (748) Google Scholar). ACE-inhibiting drugs have an antihypertensive effect and substantially lower the long-term risk of death, heart attack, stroke, coronary revascularization, heart failure, and complications related to diabetes mellitus (for review, see Ref.3.Francis G.S. N. Engl. J. Med. 2000; 342: 201-202Crossref PubMed Scopus (80) Google Scholar). ACE also inactivates bradykinin by catalyzing the cleavage of the C-terminal dipeptide from the nonapeptide hormone (4.Blais C.J. Marceau F. Rouleau J.-L. Adam A. Peptides (Elmsford). 2000; 21: 1903-1940Crossref PubMed Scopus (121) Google Scholar), and ACE inhibitor-induced cough has been attributed to inhibition of bradykinin metabolism (5.Fox A.J. Lalloo U.G. Belvisi M.G. Bernareggi M. Chung K.F. Nat. Med. 1996; 2: 814-817Crossref PubMed Scopus (257) Google Scholar). angiotensin-converting enzyme-related carboxypeptidase angiotensin I-converting enzyme angiotensin I (1.Donoghue M. Hsieh F. Baronas E. Godbout K. Gosselin M. Stagliano N. Donovan M. Woolf B. Robison K. Jeyaseelan R. Breitbart R.E. Acton S. Circ. Res. 2000; 87: 1-9Crossref PubMed Google Scholar, 2.Skeggs L.T. Kahn J.R. Shumway N.P. J. Exp. Med. 1956; 103: 295-299Crossref PubMed Scopus (748) Google Scholar, 3.Francis G.S. N. Engl. J. Med. 2000; 342: 201-202Crossref PubMed Scopus (80) Google Scholar, 4.Blais C.J. Marceau F. Rouleau J.-L. Adam A. Peptides (Elmsford). 2000; 21: 1903-1940Crossref PubMed Scopus (121) Google Scholar, 5.Fox A.J. Lalloo U.G. Belvisi M.G. Bernareggi M. Chung K.F. Nat. Med. 1996; 2: 814-817Crossref PubMed Scopus (257) Google Scholar, 6.Tipnis S.R. Hooper N.M. Hyde R. Karran E. Christie G. Turner A.J. J. Biol. Chem. 2000; 275: 33238-33243Abstract Full Text Full Text PDF PubMed Scopus (1745) Google Scholar, 7.Fernandez M. Liu X. Wouters M.A. Heyberger S. Husain A. J. Biol. Chem. 2001; 276: 4998-5004Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 8.Shapiro R. Holmquist B. Riordan J.F. Biochemistry. 1983; 22: 3850-3857Crossref PubMed Scopus (81) Google Scholar, 9.Rovere C. Barbero P. Kitabgi P. J. Biol. Chem. 1996; 271: 11368-11375Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, 10.Bunning P. Riordan J.F. Biochemistry. 1983; 22: 110-116Crossref PubMed Scopus (99) Google Scholar) angiotensin II (1.Donoghue M. Hsieh F. Baronas E. Godbout K. Gosselin M. Stagliano N. Donovan M. Woolf B. Robison K. Jeyaseelan R. Breitbart R.E. Acton S. Circ. Res. 2000; 87: 1-9Crossref PubMed Google Scholar, 2.Skeggs L.T. Kahn J.R. Shumway N.P. J. Exp. Med. 1956; 103: 295-299Crossref PubMed Scopus (748) Google Scholar, 3.Francis G.S. N. Engl. J. Med. 2000; 342: 201-202Crossref PubMed Scopus (80) Google Scholar, 4.Blais C.J. Marceau F. Rouleau J.-L. Adam A. Peptides (Elmsford). 2000; 21: 1903-1940Crossref PubMed Scopus (121) Google Scholar, 5.Fox A.J. Lalloo U.G. Belvisi M.G. Bernareggi M. Chung K.F. Nat. Med. 1996; 2: 814-817Crossref PubMed Scopus (257) Google Scholar, 6.Tipnis S.R. Hooper N.M. Hyde R. Karran E. Christie G. Turner A.J. J. Biol. Chem. 2000; 275: 33238-33243Abstract Full Text Full Text PDF PubMed Scopus (1745) Google Scholar, 7.Fernandez M. Liu X. Wouters M.A. Heyberger S. Husain A. J. Biol. Chem. 2001; 276: 4998-5004Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 8.Shapiro R. Holmquist B. Riordan J.F. Biochemistry. 1983; 22: 3850-3857Crossref PubMed Scopus (81) Google Scholar) ((7-methoxycoumarin-4-yl)acetyl-Ala-Pro-Lys(2,4-dinitrophenyl)-OH) (7-methoxycoumarin-4-yl)acetyl-Tyr-Val-Ala-Asp-Ala-Pro-Lys(2,4-dinitrophenyl)-OH matrix-assisted laser desorption ionization time-of-flight high pressure liquid chromatography 4-morpholineethanesulfonic acid 2- (cyclohexylamino)ethanesulfonic acid 3-(cyclohexylamino) propanesulfonic acid 1,3-bis[tris(hydroxymethyl)methylamino]propane Like ACE, ACE2 is expressed in endothelial cells, although its expression is restricted to fewer tissues, which include the heart, kidney, and testis (1.Donoghue M. Hsieh F. Baronas E. Godbout K. Gosselin M. Stagliano N. Donovan M. Woolf B. Robison K. Jeyaseelan R. Breitbart R.E. Acton S. Circ. Res. 2000; 87: 1-9Crossref PubMed Google Scholar). ACE2 was identified as a zinc metalloprotease due to its canonical HEXXH sequence (amino acids 374–378) (1.Donoghue M. Hsieh F. Baronas E. Godbout K. Gosselin M. Stagliano N. Donovan M. Woolf B. Robison K. Jeyaseelan R. Breitbart R.E. Acton S. Circ. Res. 2000; 87: 1-9Crossref PubMed Google Scholar), its inhibition by EDTA (6.Tipnis S.R. Hooper N.M. Hyde R. Karran E. Christie G. Turner A.J. J. Biol. Chem. 2000; 275: 33238-33243Abstract Full Text Full Text PDF PubMed Scopus (1745) Google Scholar), and its sequence identity with the catalytic residues of ACE (7.Fernandez M. Liu X. Wouters M.A. Heyberger S. Husain A. J. Biol. Chem. 2001; 276: 4998-5004Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar). The ACE inhibitors captopril, lisinopril, and enalaprilat are not inhibitors of ACE2 (1.Donoghue M. Hsieh F. Baronas E. Godbout K. Gosselin M. Stagliano N. Donovan M. Woolf B. Robison K. Jeyaseelan R. Breitbart R.E. Acton S. Circ. Res. 2000; 87: 1-9Crossref PubMed Google Scholar, 6.Tipnis S.R. Hooper N.M. Hyde R. Karran E. Christie G. Turner A.J. J. Biol. Chem. 2000; 275: 33238-33243Abstract Full Text Full Text PDF PubMed Scopus (1745) Google Scholar). The physiological and pathophysiological role of ACE2 is not yet clearly understood. To better understand the physiological role of ACE2, a detailed biochemical analysis of ACE2 substrate preference was undertaken. We reported previously that secreted recombinant ACE2 expressed in Chinese hamster ovary cells catalyzes cleavage of the C-terminal residue of the biological peptides Ang I, des-Arg9-bradykinin, neurotensin 1–13, and kinetensin (1.Donoghue M. Hsieh F. Baronas E. Godbout K. Gosselin M. Stagliano N. Donovan M. Woolf B. Robison K. Jeyaseelan R. Breitbart R.E. Acton S. Circ. Res. 2000; 87: 1-9Crossref PubMed Google Scholar). Similarly, Tipnis et al. (6.Tipnis S.R. Hooper N.M. Hyde R. Karran E. Christie G. Turner A.J. J. Biol. Chem. 2000; 275: 33238-33243Abstract Full Text Full Text PDF PubMed Scopus (1745) Google Scholar) reported that unpurified ACE2 expressed in Chinese hamster ovary cells catalyzes the hydrolysis of the C-terminal residue of Ang I and Ang II. Herein is the first report of characterization of the catalytic activity of purified ACE2. A sensitive fluorogenic substrate was developed and used to assess the dependence of ACE2 hydrolytic activity on pH and on the presence of monovalent anions. Also, ACE2 substrates were identified from screening biological peptides, and the kinetic constants were determined for hydrolysis of those peptides. The identified peptides are candidate ACE2 physiological substrates. HPLC columns were purchased from the Waters Corp. (Milford, MA). Toyopearl columns were purchased from Tosoh Biosep (Montgomeryville, PA). The peptide Mca-APK(Dnp) was synthesized by Anaspec, Inc. (San Diego, CA). Biological peptides were purchased from Sigma-Aldrich Co., Bachem Bioscience (King of Prussia, PA), and American Peptide Co. (Sunnyvale, CA). Specifically, Ang I, Ang II, and dynorphin A 1–13 were purchased from Sigma-Aldrich Co. 7-Methoxycoumarin-4-yl)acetyl-YVADAPK(2,4-dinitrophenyl)-OH (M-2195), apelin-13, β-casomorphin, des-Arg9-bradykinin, Lys-des-Arg9-bradykinin, and neurotensin 1–8 were purchased from Bachem Bioscience. An expression vector was generated encoding a secreted form of human ACE2 (1.Donoghue M. Hsieh F. Baronas E. Godbout K. Gosselin M. Stagliano N. Donovan M. Woolf B. Robison K. Jeyaseelan R. Breitbart R.E. Acton S. Circ. Res. 2000; 87: 1-9Crossref PubMed Google Scholar) (amino acids 1–740) in the pBac Pak9 vector (CLONTECH). Sf9 insect cells were infected at a multiplicity of infection of 0.1 with ACE2 baculovirus of titer 1.1 × 109 pfu/ml. A 10-liter fermentation run was carried out with SF9 cells grown to a density of 1.3 × 106 cells/ml in SF900II serum-free medium (Invitrogen), 18 mml-glutamine, and 1× antibiotic-antimycotic (from 100X stock; Invitrogen) at 27 °C. At 96 h after infection, cells were pelleted at 5000 × gcentrifugation, and the culture supernatant was collected, frozen, and stored at −80 °C. The thawed supernatant was filtered (0.2-μm filter) and loaded onto a Toyopearl QAE anion exchanger column, and the column was washed with buffer A (25 mm Tris-HCl, pH 8.0). A 0–50% gradient elution was then performed with increasing buffer B (1.0 mNaCl and 25 mm Tris-HCl, pH 8.0) using a total of 5 column volumes. The ACE2-containing fractions, as detected by Coomassie Blue-stained SDS-PAGE, were pooled, and (NH4)2SO4 was added to a final concentration of 1.0 m. The sample was then loaded onto a Toyopearl Phenyl column. After loading, the column was washed with buffer C (1.0 m(NH4)2SO4 and 25 mmTris-HCl, pH 8.0) using 5 column volumes and then gradient-eluted with buffer A (0–100%). The ACE2-containing fractions, as detected by Coomassie Blue-stained SDS-PAGE, were pooled and dialyzed against buffer A at 4 °C overnight. The dialyzed ACE2 protein sample was sequentially loaded onto MonoQ column (Amersham Biosciences) and gradient-eluted with buffer B. The ACE2-containing fractions from the MonoQ column, as detected by Coomassie Blue-stained SDS-PAGE, were concentrated with a Centricon (Millipore Corp., Bedford, MA) concentrator, with a molecular mass cutoff of 30 kDa. The concentrated sample was loaded onto a TSK G3000SWxl size exclusion column and eluted with buffer A. Mca-APK(Dnp) was dissolved in 100% Me2SO and quantitated by measuring absorbance at 350 nm using an extinction coefficient of 15,000m−1 cm−1. All reactions were performed in microtiter plates with a 100-μl total volume at ambient temperature. To each well, we added 75 μl of salt (NaCl, NaF, NaBr, or KCl), 5.0 μl of buffer (50 mm, final concentration), and 10 μl of Mca-APK(Dnp) (50 μm, final concentration), and the reaction was initiated by the addition of 10 μl of ACE2 (0.15 nm, final concentration). The buffers used in the pH dependence studies were sodium acetate, MES, bis-Tris propane, CHES, and CAPS, and the buffer used in the anion dependence studies was MES. The final Me2SO concentration in the assay was 0.7%. The assay was monitored continuously by measuring the increase in fluorescence (excitation = 320 nm, emission = 405 nm) upon substrate hydrolysis using a Polarstar Galaxy fluorescence plate reader (BMG Lab Technologies, Durham, NC). Initial velocities were determined from the rate of fluorescence increase over the 15–60-min time course corresponding to ≤10% product formed. The pH was found to have no significant effect on product fluorescence across the range of pH 5 to pH 10 in the assay buffers. Reactions were performed in microtiter plates at ambient temperature. To each well, we added 5 μl of 1 mm peptide (50 μm, final concentration) and 45 μl of buffer (50 mm MES, 300 mm NaCl, 10 μmZnCl2, and 0.01% Brij-35 pH 6.5), and reaction was initiated by the addition of 50 μl of 100 nm ACE2 (50 nm, final concentration) or buffer (control). Reactions were performed at room temperature for 2 h and quenched with 20 μl of 0.5 m EDTA. Samples were then analyzed by MALDI-TOF mass spectrometry for detection of hydrolysis and determination of products formed. Mass spectrometry was performed on a Voyager Elite biospectrometry MALDI-TOF spectrometer (PerSeptive Biosystems, Framingham, MA) as described previously (1.Donoghue M. Hsieh F. Baronas E. Godbout K. Gosselin M. Stagliano N. Donovan M. Woolf B. Robison K. Jeyaseelan R. Breitbart R.E. Acton S. Circ. Res. 2000; 87: 1-9Crossref PubMed Google Scholar). The peptides that were found to be hydrolyzed by ACE2 were re-assayed under the same conditions in the presence of a high concentration of a potent, specific inhibitor of ACE2 2E. Calderwood, N. Dales, A. Gould, B. Guan, T. Ocain, and M. Patane, unpublished results.to confirm specific cleavage by this protease. Rates of substrate hydrolysis were determined by reversed phase chromatography using a capillary HPLC system (Agilent, Palo Alto, CA). Reactions were performed in 100 μl in microtiter plates at ambient temperature. Reactions were initiated by the addition of 50 μl of ACE2 (0.025–0.70 nm, final concentration) to 50 μl of peptide in assay buffer (50 mmMES, 300 mm NaCl, 10 μm ZnCl2, and 0.01% Brij-35, pH 6.5). Reactions were performed at room temperature for 0, 15, 22.5, or 30 min and quenched by the addition of 10 μl of 0.5 m EDTA. Substrate concentrations ranged from 0.8–2000 μm, and hydrolysis was limited to ≤15% product formed (initial velocity conditions). Concentrations of the biological peptides were determined spectrophotometrically. Substrate and product peptides were resolved on a YMC ODS-A 1.0 × 50-mm 120A 5-μm column using a gradient of 10–45% B (A, water/0.1% trifluoroacetic acid (v/v); B, acetonitrile/0.1% trifluoroacetic acid (v/v)) and detected by absorbance at 215 nm. The peptide Mca-APK(Dnp) and its reaction product were resolved in the same manner using a gradient of 15–65% B and detected by absorbance at 350 nm. Injection volumes ranged from 0.5–20 μl. The extent of hydrolysis was determined from the areas of the substrate and product peaks (area of product peak/(area of product peak + area of substrate peak)) and converted to micromoles of product formed. Initial velocities (v) of substrate hydrolysis were calculated from the slopes of micromoles of product formed versus time. Initial velocities (v) were plotted versus substrate concentration and fit to the Michaelis-Menten equation (v =V max[S]/K m + [S]) using Grafit software (Erithacus Software Ltd., Surrey, United Kingdom). Turnover numbers (k cat) were calculated from the equation k cat = V max/[E], using a calculated ACE2 molecular mass of 85,314 Da and considering the enzyme sample to be essentially pure and fully active. Recombinant soluble human ACE2, encoding amino acids 1–740 of the 805-amino acid full-length enzyme and deleting the C-terminal transmembrane domain, was expressed in Chinese hamster ovary cells and isolated to ∼90% purity by SDS-PAGE (as described previously, Ref.1.Donoghue M. Hsieh F. Baronas E. Godbout K. Gosselin M. Stagliano N. Donovan M. Woolf B. Robison K. Jeyaseelan R. Breitbart R.E. Acton S. Circ. Res. 2000; 87: 1-9Crossref PubMed Google Scholar). This ACE2 sample was used to screen a number of commercially available intramolecularly quenched fluorescent peptides to identify a suitable fluorescent substrate for initial enzyme characterization. The caspase-1 substrate Mca-YVADAPK(Dnp) was found to be hydrolyzed by ACE2, as measured by a time-dependent increase in fluorescence (excitation = 320 nm, emission = 405 nm). Analysis of the reaction products by MALDI-TOF mass spectrometry indicated hydrolysis of the Pro-Lys(2,4-dinitrophenyl) peptide bond. A truncated peptide with more efficient intramolecular fluorescence quenching, Mca-APK(Dnp), was synthesized and assayed as an ACE2 substrate with the goal of improving the fluorescence signal of the assay. Complete hydrolysis of 40 μm Mca-APK(Dnp) resulted in a 300-fold fluorescence increase over background, whereas complete hydrolysis of the same concentration of Mca-YVADAPK(Dnp) resulted in a 21-fold increase over background. The Mca-APK(Dnp) substrate is hydrolyzed by ACE2 and was used for characterization of the enzyme activity. Recombinant soluble human ACE2 was expressed in Sf9 insect cells and isolated to >98% purity, based on SDS-PAGE (Fig. 1 C), by a four-step chromatography protocol. The purified protein sample was confirmed to be ACE2 by peptide mapping of trypsin-digested protein, analyzed by MALDI-TOF mass spectrometry (data not shown). The molecular mass of the purified ACE2 (89.6 kDa, as determined by MALDI-TOF mass spectrometry) is greater than that predicted from the peptide sequence (85.314 kDa). The higher molecular mass is likely to be due to glycosylation, as has been reported for ACE2 (6.Tipnis S.R. Hooper N.M. Hyde R. Karran E. Christie G. Turner A.J. J. Biol. Chem. 2000; 275: 33238-33243Abstract Full Text Full Text

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Pituitary Adenylate Cyclase-Activating Polypeptide and Its Receptors: From Structure to Functions

2000-06-01

David Vaudry , Bruno J. Gonzalez , Magali Basille +3 more

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a 38-amino acid peptide that was first isolated from ovine hypothalamic extracts on the basis of its ability to stimulate cAMP formation in anterior … Pituitary adenylate cyclase-activating polypeptide (PACAP) is a 38-amino acid peptide that was first isolated from ovine hypothalamic extracts on the basis of its ability to stimulate cAMP formation in anterior pituitary cells. PACAP belongs to the vasoactive intestinal polypeptide (VIP)-glucagon-growth hormone releasing factor-secretin superfamily. The sequence of PACAP has been remarkably well conserved during the evolution from protochordate to mammals, suggesting that PACAP is involved in the regulation of important biological functions. PACAP is widely distributed in the brain and peripheral organs, notably in the endocrine pancreas, gonads, and respiratory and urogenital tracts. Characterization of the PACAP precursor has revealed the existence of a PACAP-related peptide whose activity remains unknown. Two types of PACAP binding sites have been characterized. Type I binding sites exhibit a high affinity for PACAP and a much lower affinity for VIP whereas type II binding sites have similar affinity for PACAP and VIP. Molecular cloning of PACAP receptors has shown the existence of three distinct receptor subtypes, the PACAP-specific PAC1 receptor, which is coupled to several transduction systems, and the two PACAP/VIP-indifferent VPAC1 and VPAC2 receptors, which are primarily coupled to adenylyl cyclase. PAC1 receptors are particularly abundant in the brain and pituitary and adrenal glands whereas VPAC receptors are expressed mainly in the lung, liver, and testis. The wide distribution of PACAP and PACAP receptors has led to an explosion of studies aimed at determining the pharmacological effects and biological functions of the peptide. This report reviews the current knowledge concerning the multiple actions of PACAP in the central nervous system and in various peripheral organs including the endocrine glands, the airways, and the cardiovascular and immune systems, as well as the different effects of PACAP on a number of tumor cell types.

Peptidergic neurones

1980-04-01

Tomas Hökfelt , Ӧlle Johansson , Å. Ljungdahl +2 more

Cholecystokinin: Clinical aspects of the new biology

2025-06-25

Jens F. Rehfeld | Journal of Internal Medicine

Abstract Cholecystokinin (CCK) is a classic gut hormone that has been known for almost a century to regulate gallbladder emptying, pancreatic enzyme secretion, and gastrointestinal motor activity. In 1968, the … Abstract Cholecystokinin (CCK) is a classic gut hormone that has been known for almost a century to regulate gallbladder emptying, pancreatic enzyme secretion, and gastrointestinal motor activity. In 1968, the CCK structure was identified by Viktor Mutt and Erik Jorpes from porcine gut extracts as a peptide of 33 amino acid residues. Based on that structure, physiological, immunochemical, molecular, and cell biological research has since expanded the insight into the biology of CCK remarkably. Thus, CCK was the first identified intestinal satiety signal to the brain. Moreover, the CCK gene is now known to be expressed in different molecular forms not only in the gut, but very much so in central and peripheral neurons, in addition to extra‐intestinal endocrine cells, immune cells, cardiomyocytes, spermatogenic cells, and certain fat cells. Accordingly, CCK peptides function not only as hormones. They are also neurotransmitters, paracrine growth and satiation factors, anti‐inflammatory cytokines, incretins, adipokins, myokines, potential fertility factors, and tumor markers. Consequently, CCK biology has now opened windows for insights into pathophysiology with diagnostic and therapeutic possibilities in metabolic disorders (obesity, eating disorders, and diabetes mellitus), gallbladder disease, neuropsychiatric diseases (cerebral tumors, memory, and anxiety disorders), cardiac diseases (prognosis in heart failure), neuroendocrine and pediatric tumors, as well as perhaps infertility.

Ocular safety of glucagon-like peptide-1 receptor agonists: insights and unanswered questions. Authors’ reply

2025-06-24

Maria Cecilia Bahit , C. Michael Gibson , Martyna Kuleta +4 more | Polskie Archiwum Medycyny Wewnętrznej

Ocular safety of glucagon-like peptide-1 receptor agonists: insights and unanswered questions

2025-06-24

Artur Dziewierz , Renata Rajtar‐Salwa , Francesco Pelliccia | Polskie Archiwum Medycyny Wewnętrznej

Molecular and cellular basis of mu-opioid receptor signaling: mechanisms underlying tolerance and dependence development

2025-06-24

Michael Swingler , Martina Donadoni , Ellen M. Unterwald +2 more | Frontiers in Neuroscience

Opioids, while highly effective for pain management, are among the most addictive substances, contributing significantly to the global opioid crisis. Opioid use disorder (OUD) affects millions, with synthetic opioids like … Opioids, while highly effective for pain management, are among the most addictive substances, contributing significantly to the global opioid crisis. Opioid use disorder (OUD) affects millions, with synthetic opioids like fentanyl exacerbating the epidemic due to their potency and widespread illicit availability. Opioids exert their effects through opioid receptors (ORs), primarily the mu opioid receptor (MOR), which mediates both therapeutic analgesia and adverse effects such as euphoria, dependence, and tolerance. Chronic opioid use leads to cellular adaptations, including receptor phosphorylation, desensitization, and recruitment of β-arrestin, which uncouple MOR from downstream signaling pathways. These changes, along with compensatory upregulation of adenylyl cyclase (AC) and cAMP signaling, underlie the development of tolerance, dependence, and withdrawal, however the exact signaling pathways responsible remain unknown. Emerging research highlights the role of neuroinflammation, genetic polymorphisms, and alternative splicing of MOR isoforms in modulating opioid responses and vulnerability to OUD. Current treatments for OUD, such as methadone, buprenorphine, and naltrexone, are limited by compliance, access, and relapse rates. Novel therapeutic strategies, including biased MOR agonists, opioid vaccines, and splice variant-specific agonists, offer promise for safer pain management and reduced abuse liability. However, a deeper understanding of opioid receptor signaling, neuroimmune interactions, and genetic factors is essential to develop more effective interventions. This review explores the molecular mechanisms of opioid tolerance, dependence, and withdrawal, emphasizing the need for innovative approaches to address the opioid crisis and improve treatment outcomes.

More Than Three Decades After Discovery of the Neuroprotective Effect of PACAP, What Is Still Preventing Its Clinical Use?

2025-06-21

Asma Cherait , Xavier Xifró , Dóra Reglődi +1 more | Journal of Molecular Neuroscience

Discovered in 1989, pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide with strong neuroprotective properties, as shown in various neurodegenerative preclinical models of Parkinson, Alzheimer, or Huntington diseases. PACAP neuroprotection … Discovered in 1989, pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide with strong neuroprotective properties, as shown in various neurodegenerative preclinical models of Parkinson, Alzheimer, or Huntington diseases. PACAP neuroprotection has also been reported in animal models of cerebral ischemia and traumatic brain injury. The neuroprotective effect of PACAP occurs through its capacity to modulate most of the multiphasic aspects of neuronal diseases, such as oxidative stress, neuronal cell death, and inflammation. However, more than three decades after its discovery, and although PACAP neurotrophic and neuroprotective activities have now been largely documented, its clinical use is still awaited. Thus, the aim of this manuscript is to discuss the main reasons which limit the use of PACAP as a therapeutic agent for the treatment of neuronal diseases. To achieve this objective, an opinion survey has been conducted among experts in the field of PACAP, and a bibliographic investigation was carried out.

Retraction: GABA induces the differentiation of small into large cholangiocytes by activation of Ca2+/CaMK I-dependent adenylyl cyclase 8

2025-06-19

Romina Mancinelli , Antonio Franchitto , Shannon Glaser +7 more | Hepatology

Central neuropeptides as key modulators of astrocyte function in neurodegenerative and neuropsychiatric disorders

2025-06-19

Mengjie Yang , Min Jia , Meng Cai +3 more | Psychopharmacology

Central neuropeptides are small proteins or peptides primarily produced and released by neurons. They act as neurotransmitters, neuromodulators, and neuroregulators within the central nervous system (CNS). Numerous studies have demonstrated … Central neuropeptides are small proteins or peptides primarily produced and released by neurons. They act as neurotransmitters, neuromodulators, and neuroregulators within the central nervous system (CNS). Numerous studies have demonstrated that these neuropeptides play a role in both normal neurophysiological processes and pathological conditions. Astrocytes, the most abundant glial cells in the CNS, are crucial for maintaining brain function and health, and they contribute significantly to the development of CNS disorders-especially neurodegenerative and neuropsychiatric diseases. Previous research suggests that central neuropeptides influence astrocyte activity by regulating their proliferation, morphology, and secretory functions, among other aspects, thereby impacting the pathogenesis of these disorders. Based on preclinical evidence, both central neuropeptides and their receptors are emerging as promising targets for treating CNS disorders. In this review, we examine the effects of select central neuropeptides-including neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP), cholecystokinin (CCK), corticotropin-releasing hormone (CRH), angiotensin (Ang), oxytocin (OXT), orexin (OX)/hypocretin (HCRT), and glucagon-like peptide-1 (GLP-1)-on astrocyte state transitions. Our aim is to provide novel insights that could inform the clinical treatment of neurodegenerative and neuropsychiatric disorders.

Determinants of Improved CGRP Peptide Binding Kinetics Revealed by Enhanced Molecular Simulations

2025-06-17

Ceren Kılınç , Katie M. Babin , Augen A. Pioszak +1 more | bioRxiv (Cold Spring Harbor Laboratory)

ABSTRACT Peptides are desirable therapeutics due to their inherent potency, safety, cost-effectiveness and ability to engage large or more complex protein surfaces. Slower kinetics of protein-peptide (un)binding can directly influence … ABSTRACT Peptides are desirable therapeutics due to their inherent potency, safety, cost-effectiveness and ability to engage large or more complex protein surfaces. Slower kinetics of protein-peptide (un)binding can directly influence their drug efficacy and duration of action, in part by improving plasma stability of the peptide. The CLR:RAMP1 complex and its endogenous agonist peptide CGRP are of particularly high interest because of their central role in migraine pathophysiology. A better understanding of peptide binding mechanisms is needed for the development of next-generation peptide-based drugs with optimized kinetic properties. In this study, we comparatively analyze constructs of native CGRP and “ssCGRP”, an engineered variant with 430-fold longer residence time on the CLR:RAMP1 complex. Using large-scale computational resources and our high-dimensional weighted-ensemble algorithm, we then thoroughly sample and compare unbinding path ensembles for the two peptides. This elucidates the basis of the engineered residence time enhancement for ssCGRP and provides a detailed view of the intra- and intermolecular stabilizing interactions for both peptides in the bound ensemble and along the unbinding transition path. The bias-free nature of the sampling approach in combination with Markov state modeling allows for the calculation of committor values and the first analysis of protein-peptide binding transition state ensembles. Through analysis of the unbinding committor, we find that ssCGRP(27–37) also demonstrates enhanced ligand recapture of intermediate unbinding conformations and samples a more heterogeneous bound-state ensemble that entropically stabilizes the bound basin. This study shows the molecular determinants of peptide residence time at CLR:RAMP1 and provides valuable insight for the design of long-acting peptide therapeutics.

Alpha-CGRP as a specific response mediator during acute myocardial infarction in humans: findings from an observational longitudinal study

2025-06-16

Gorka Garate , L. Gangas , Juan Manuel de Jesús Cortés de la Torre +3 more | Frontiers in Cardiovascular Medicine

Introduction Calcitonin gene-related peptide (CGRP), particularly its alpha isoform, might play a role in restoring physiological cardiovascular functioning. While its involvement in acute myocardial infarction (AMI) pathophysiology has been suggested, … Introduction Calcitonin gene-related peptide (CGRP), particularly its alpha isoform, might play a role in restoring physiological cardiovascular functioning. While its involvement in acute myocardial infarction (AMI) pathophysiology has been suggested, human data remain scarce. This study analyzed circulating alpha-CGRP levels during AMI, comparing them to healthy controls (HC) and post-AMI resolution levels. Methods A total of 26 AMI patients and 26 age- and sex-matched HC were recruited. Blood samples were collected from patients within four hours of AMI onset and, when possible, six months post-event. Alpha-CGRP serum concentrations were measured using a validated ELISA assay. Results Alpha-CGRP levels were significantly higher in AMI patients at admission (mean ± SD: 96.0 ± 77.4 pg/ml) compared to HC (42.0 ± 25.8 pg/ml, p &lt; 0.0001), with an average increase of 129%. Among nine patients available for follow-up, levels normalized to the HC range (45.1 ± 26.7 pg/ml, p = 0.011). Patients with poor outcomes had numerically lower alpha-CGRP levels (72.6 ± 37.2 pg/ml) than those with a satisfactory resolution (100.3 ± 82.5 70.6 pg/ml; p = 0.241). Discussion Alpha-CGRP is acutely elevated during AMI, likely as a compensatory vasodilator response to ischemia. Its post-AMI normalization suggests a transient protective mechanism. Further research is needed to explore its role in AMI-related pathophysiology and usefulness as a therapeutic agent.

EXPRESS: Visceral pain-related acute actions of cerulein on mouse and human sensory neurons

2025-06-16

Sachin Goyal , Nesia A. Zurek , Reza Ehsanian +7 more | Molecular Pain

Cerulein is an orthologue of cholecystokinin, which is often used to induce acute pancreatitis in pre-clinical studies. In these models, animals show signs of pain, and this is the most … Cerulein is an orthologue of cholecystokinin, which is often used to induce acute pancreatitis in pre-clinical studies. In these models, animals show signs of pain, and this is the most common complaint of patients with acute pancreatitis. However, little is known about how this pain is mediated, the role of cerulein murine pain responses, or its relevance to human pancreatitis pain. We injected 25 or 50 µg/kg cerulein intraperitoneally into male and female mice and assessed pain behaviors using the von Frey test of mechanical hypersensitivity. The excitability of mouse and human visceral DRG neurons was assessed using whole-cell patch-clamp electrophysiology. Pharmacology was performed using commercial antagonists of cholecystokinin A or B receptors. We show that pain behaviors developed similarly in male and female cerulein-injected mice and that visceral DRG from these mice exhibited increased excitability compared to controls. Direct application of cerulein to T8-L2 mouse and human DRG showed increased excitability compared to controls consistent with DRG from cerulein-injected mice. The actions of cerulein on visceral DRG neurons were attributed to CCKA, but not CCKB receptor. A similar DRG response to cerulein was observed in a human DRG. These findings highlight the importance of the cholecystokinin system, particularly the CCK-A receptor, to visceral pain including pancreatitis through direct sensitization of visceral dorsal root ganglia neurons from mice or humans.

351-OR: Plasticity in Proglucagon Processing and Secretion by Alpha Cells

2025-06-13

Canqi Cui , Sarah M. Gray , Paul A. Grimsrud +7 more | Diabetes

Introduction and Objective: Glucagon-like peptide (GLP-1) and glucagon stimulate insulin secretion by engaging β-cell GLP-1 receptors. The degree to which alpha-cells produce GLP-1 from proglucagon remains debatable. We hypothesized that … Introduction and Objective: Glucagon-like peptide (GLP-1) and glucagon stimulate insulin secretion by engaging β-cell GLP-1 receptors. The degree to which alpha-cells produce GLP-1 from proglucagon remains debatable. We hypothesized that alpha-cells are able to vary proglucagon processing from glucagon to GLP-1, providing a more potent GLP-1R ligand to enhance insulin secretion. Methods: To test this, we developed a novel assay to accurately quantify GLP-1 levels in islets and generated mouse models with alpha-cell deletion of either Pcsk1 (which generates GLP-1) or Pcsk2 (which generates glucagon), alone and in combination. Results: Using a mass-spectrometry based assay, active GLP-1 was measurable in both mouse and human islets, and levels increased in models of metabolic stress. Deletion of Pcsk1 in alpha-cells nearly eliminated active GLP-1 from mouse islets, but these animals had insulin secretion and glucose tolerance comparable to controls, even with high-fat feeding. Deletion of Pcsk2 reduced islet and plasma glucagon levels and increased Pcsk1 expression and islet GLP-1 levels. However, insulin secretion and glucose tolerance were improved. The enhanced insulin secretion was eliminated by the GLP-1R antagonist exendin-9, supporting greater GLP-1 production as the mechanism for improved β-cell function. With α-cell knockout of both Pcsk1 and Pcsk2, islet GLP-1 and glucagon were substantially reduced, leading to impaired insulin secretion and glucose intolerance. Human islets had nearly 10-fold greater GLP-1 content than mouse islets and levels correlated with glucose-stimulated insulin secretion across age, sex, BMI, and A1C. Conclusion: These results indicate that islet proglucagon peptides are necessary for normal glucose tolerance and support a model whereby varying amounts of islet proglucagon peptides regulate insulin secretion. Disclosure C. Cui: None. S.M. Gray: Employee; Sage Therapeutics. Stock/Shareholder; Sage Therapeutics, Fractyl Health, Inc. P.A. Grimsrud: None. D.C. Leander: None. K.M. El: None. J. Becker: None. A. Hoofnagle: None. G. Zhang: None. D. D'Alessio: Consultant; Arrowhead Pharmaceuticals, Inc. Other Relationship; Eli Lilly and Company. Consultant; Gasherbrum Bio, Inc. Stock/Shareholder; MBX Biosciences. Consultant; Structure Therapeutics, Inc. Advisory Panel; Sun Pharmaceutical Industries Ltd. J. Campbell: Research Support; Eli Lilly and Company, Novo Nordisk. Advisory Panel; Structure Therapeutics, Inc. Research Support; Structure Therapeutics, Inc. Consultant; Arrowhead Pharmaceuticals, Inc. Advisory Panel; Boehringer-Ingelheim, Neurocrine, Roche Pharmaceuticals, Prostasis. Research Support; Merck & Co., Inc.

A GLP‐1R/Y1 receptor/Y2 receptor triple agonist decreases fentanyl‐evoked dopamine release in the nucleus accumbens and attenuates fentanyl taking and seeking in rats

2025-06-02

Antonia Caffrey , Enzo Lavecchia , Kylie S. Chichura +3 more | British Journal of Pharmacology

Abstract Background and Purpose Emerging literature indicates that simultaneously targeting glucagon‐like peptide‐1 receptors (GLP‐1Rs) and neuropeptide Y receptors (Y 1 /Y 2 ) may represent a new pharmacotherapeutic approach to … Abstract Background and Purpose Emerging literature indicates that simultaneously targeting glucagon‐like peptide‐1 receptors (GLP‐1Rs) and neuropeptide Y receptors (Y 1 /Y 2 ) may represent a new pharmacotherapeutic approach to treating opioid use disorder (OUD). The overall goal of this study was to screen the efficacy of GEP12, a novel GLP‐1R/Y 1 receptor/Y 2 receptor triple agonist, to reduce voluntary fentanyl taking and seeking. Experimental Approach Rats were allowed to self‐administer fentanyl (2.5 μg kg −1 , i.v.) for 21 days. Rats were then pretreated with vehicle or GEP12 (1.57 or 12.53 μg kg −1 , i.p.) prior to fentanyl self‐administration test sessions. Opioid taking was then extinguished and rats were pretreated with vehicle or GEP12 (1.57 or 12.53 μg kg −1 , i.p.) prior to subsequent reinstatement test sessions. Key Results GEP12 reduced fentanyl taking in both male and female rats and shifted the fentanyl self‐administration dose–response curve downward. Importantly, we identified behaviourally selective doses of GEP12 that were well‐tolerated in fentanyl‐experienced rats. GEP12 also reduced fentanyl seeking during abstinence in both male and female rats at doses that did not alter food intake or produce adverse malaise‐like effects. To identify a central mechanism underlying the efficacy of GLP‐1R/Y 1 receptor/Y 2 receptor triple agonists, we showed that systemic GEP12 penetrated the brain and distributed to the mesolimbic reward system. Using in vivo fibre photometry, we discovered that GEP12 reduced fentanyl self‐administration‐evoked dopamine release in the nucleus accumbens. Conclusions and Implications Together, these findings support the continued development of GLP‐1R/Y 1 receptor/Y 2 receptor triple agonists as a novel class of pharmacotherapies for treating OUD.

Pharmacological Characterization of Vampire Bat-Derived CGRP at the Human CGRP Receptor in the Xenopus oocyte system

2025-06-01

Kathleen Carleer , K. B. Raval , Slavica Tudzarova +1 more | Toxicon

Chemokine CCL12 in trigeminal ganglion contributes to CFA-induced mechanical allodynia in mice

2025-06-01

Xiaoxia Ma , Lijia Mai , Yifan He +4 more | Neuroscience

Flush with insight: Decoding GPCR crosstalk in the spinal defecation center

2025-06-01

Nil Casajuana‐Martin , Eli Fritz McDonald , M. Madan Babu | Cell chemical biology

Multifaceted role and regulation of neuropeptide Y in the ovary of wall lizard, Hemidactylus flaviviridis

2025-06-01

Vishesh Chauhan , Umesh Rai , Mamta Tripathy +1 more | General and Comparative Endocrinology

Pathogenic role of CD169+ macrophages in neuronal loss and motor decline in NMO mice

2025-06-01

Yuko Morita , Oluwaseun Fatoba , Takahide Itokazu +1 more | Experimental Neurology

Neuromyelitis optica (NMO) is a severe autoimmune inflammatory disease characterized by debilitating symptoms, such as blindness or paralysis, often following a single acute attack. However, effective acute treatments to prevent … Neuromyelitis optica (NMO) is a severe autoimmune inflammatory disease characterized by debilitating symptoms, such as blindness or paralysis, often following a single acute attack. However, effective acute treatments to prevent long-term sequelae are currently limited. This study aimed to investigate the role of CD169-expressing macrophages during the acute phase of NMO. We developed an NMO mouse model by injecting high-affinity AQP4-IgG with human complement into the striatum, inducing NMO-like lesions marked by astrocyte loss and infiltration of microglia/macrophages and neutrophils. Immunohistochemical analyses revealed that CD169-expressing macrophages were the predominant infiltrating cells within the lesion core. Based on this finding, we explored the therapeutic potential of blocking CD169 function to mitigate NMO. CD169+ macrophages were activated by astrocytopathy, partially through SYK signaling, leading to significant neuronal loss and motor deficits. Treatment with an anti-CD169 antibody significantly reduced neuronal loss, improved motor function, and inhibited the phagocytic activity of CD169+ macrophages. Our findings demonstrate that CD169-expressing macrophages play a critical role in exacerbating tissue damage and functional decline during the acute phase of NMO. Targeting CD169 signaling may represent a promising therapeutic strategy to reduce pathological phagocytosis and prevent secondary injury in NMO.

Identification and Antiproliferative Effect of Syngnathus schlegeli Extracts on Benign Prostatic Hyperplastic Cells

2025-06-01

Bingna Cai , Xinjian Qu , Ailing Duan +7 more | Journal of Food Science

ABSTRACT Pipefish, a traditional tonic in Chinese food, has attracted attention from both scientific and industrial interest for its potential protective effects on the prostate. The research investigates the structural … ABSTRACT Pipefish, a traditional tonic in Chinese food, has attracted attention from both scientific and industrial interest for its potential protective effects on the prostate. The research investigates the structural characteristics and anti‐prostatic hyperplasia properties of petroleum ether extract (PE) from Syngnathus schlegeli . PE contained 1776 distinct lipid compounds, with phospholipids accounting for as much as 63.41% of the total. Among these phospholipids, the relative contents of lysolipid phosphatidylcholine and phosphatidylserine (PS) are relatively high, at 40.73% and 6.02%, respectively. PE upregulated the expression levels of Bax, p21WAF1/Cip1, and p53 proteins while downregulating Cyclin D1 and CDK2 proteins in TP‐induced RWPE‐1 cells. This modulation resulted in cell cycle arrest and a subsequent inhibition of cell proliferation. Transcriptome analysis revealed that PE inhibited integrin ITGB3, thereby disrupting ECM‐receptor interaction. This disruption affects cytoskeletal remodeling and focal adhesion, while also inhibiting the downstream PI3K‐Akt signaling pathway. Consequently, these effects impede the progression of TP‐induced benign prostatic hyperplasia (BPH). Notably, saturated PS exhibited a strong affinity for ITGB3 and could form stable complexes. These results indicate that PS compounds in PE have potential antiproliferative effects on BPH and could serve as a promising active compound. Practical Application : The pipefish extract PE obtained in this study demonstrates significant inhibitory effects on BPH while exhibiting low toxicity. This suggests a promising potential for its development as a functional food aimed at enhancing male reproductive health, addressing the healthcare needs of a significant portion of middle‐aged and elderly men.

A DNA Vaccine Against Proadrenomedullin N-Terminal 20 Peptide (PAMP) Reduces Angiogenesis and Increases Lymphocyte and Macrophage Infiltration but Has No Effect on Tumor Burden in a Mouse Model of Lung Metastasis

2025-05-30

Tom Kalathil Raju , Srdan Tadic , Pablo Garrido +4 more | Vaccines

Background/Objectives: Nucleic acid-based anticancer vaccines are becoming a very active field in the fight against cancer. Here, our goal was to generate an oral DNA vaccine targeting the angiogenic peptide, … Background/Objectives: Nucleic acid-based anticancer vaccines are becoming a very active field in the fight against cancer. Here, our goal was to generate an oral DNA vaccine targeting the angiogenic peptide, proadrenomedullin N-terminal 20 peptide (PAMP). Methods: An expression plasmid (PcPAMP) was generated by fusing the tetanus toxin epitopes P2 and P30 to the mouse PAMP sequence to counteract self-tolerance, and the empty plasmid was used as a negative control (PcNeg). The plasmids were introduced into Salmonella typhimurium bacteria that were then transformed into bacterial ghosts. C57BL/6J mice were orally immunized with the ghosts five times at 2-week intervals. Then, B16-F10 melanoma cells were injected into the tail vein to generate lung metastases. Furthermore, naïve CD4+ T cells were exposed to PAMP, and their secretome was analyzed by proximity extension assays. Results: Significant levels of anti-PAMP immunoglobulins were detected in the blood of PcPAMP-vaccinated mice and their levels of spleen CD8+ T cells were significantly higher than in those treated with PcNeg, indicating that self-tolerance was effectively broken. Although the number and size of lung metastases was similar between both experimental groups, there was a significant reduction in intratumoral angiogenesis and in cancer cell proliferation index in the PcPAMP group. Furthermore, these animals showed an intense infiltration of lymphocytes, including regulatory T cells, and M2-like macrophages into the metastases, that was not evident in the PcNeg group. In addition, PAMP induced upregulation of IL1β, IL6, IL7, IL12, IL27, TNFα, and FGF21, and downregulation of IL16 in naïve CD4+ T cells. Conclusions: Although the vaccine was not effective in reducing tumor growth, new proliferative and immune functions have been described for PAMP. These new functions include induction of melanoma proliferation and modulation of lymphocyte and macrophage tumor infiltration dynamics.

Correction: Gastrin exerts a protective effect against myocardial infarction via promoting angiogenesis

2025-05-29

Jinjuan Fu , Yuanjuan Tang , Zhen Zhang +3 more | Molecular Medicine

Endotrophin: Analysis of a fibroinflammatory biomarker during breast cancer therapy.

2025-05-28

Beate S. Santos , Dawei Bu , Ethan Johnson +3 more | Journal of Clinical Oncology

e15056 Background: A major challenge in breast cancer research is identifying actionable biomarkers that enable the precise molecular characterization of complex metabolic and immunological interactions. Endotrophin (ETP) is a proteolytic … e15056 Background: A major challenge in breast cancer research is identifying actionable biomarkers that enable the precise molecular characterization of complex metabolic and immunological interactions. Endotrophin (ETP) is a proteolytic fragment of collagen VIα3 associated with inflammation and fibrosis that has been linked to cardiometabolic outcomes. Elevated ETP levels have been observed in patients with breast cancer. Also, pre-clinical studies have demonstrated that targeting ETP improves cancer outcomes. The dynamic response of circulating ETP levels to cancer treatments remains unknown. Methods: This study aims to evaluate blood ETP levels in breast cancer patients undergoing cancer therapy or surgery. We prospectively collected blood samples (n = 102) from patients treated with three modalities: (1) neoadjuvant therapy (15 patients); (2) up-front surgery (12 patients); and systemic therapy for metastatic breast (9 patients). Plasma samples were obtained at baseline and during each treatment cycle, up to a maximum of six cycles, or pre- and post-surgery. ETP levels were measured using an enzyme-linked immunosorbent assay. We excluded patients with active cardiac or renal disease, uncontrolled diabetes (A1c > 8), or infectious/inflammatory conditions requiring therapy. Enrollment began in January 2024 and is ongoing at the SCCC. Results: Comparative analyses of breast cancer subtypes revealed that estrogen receptor positive (ER+) patients had significantly higher baseline and overall ETP levels than triple-negative (TNBC) patients (baseline medians 17.7 ng/mL vs. 9.5 ng/mL for ER+ v. TNBC, p = 0.03; overall medians 31.3, 19.0, 19.2 ng/mL for ER+, HER2+, TNBC, respectively; p = 0.0003 v. TNBC+; p = 0.04 v. HER2+). ETP levels in metastatic breast cancer patients were significantly higher compared to those undergoing neoadjuvant therapy (p < 0.0001) and up-front surgery (p = 0.003). In the metastatic setting, ETP levels demonstrated a strong correlation with treatment response. Declining ETP levels were associated with favorable outcomes, whereas rising or fluctuating levels indicated disease progression or poor therapeutic response. Notably, this correlation was not observed in the neoadjuvant or surgical settings. Conclusions: Plasma ETP levels were readily detectable in breast cancer patients, they were significantly elevated in ER+ disease and tracked with the response to therapy in the metastatic setting. ETP levels may be a useful biomarker to guide therapeutic strategies for existing systemic therapies, and should be further explored as a predictive biomarker for metabolic and inflammatory therapies, especially ETP-blocking agents.

99mTc-Labeled Diarylpyrazoles for Single-Emission Computer Tomography Imaging of Neurotensin Receptor-Positive Tumors: A Comparative Preclinical Study

2025-05-27

Roman Potemkin , Simone Maschauer , Harald Hübner +4 more | Pharmaceutics

Background/Objectives: Neurotensin receptors (NTSRs), members of the G protein-coupled receptor (GPCR) family, have been found to be overexpressed in several types of human cancers, including breast, colon, lung, liver, prostate, … Background/Objectives: Neurotensin receptors (NTSRs), members of the G protein-coupled receptor (GPCR) family, have been found to be overexpressed in several types of human cancers, including breast, colon, lung, liver, prostate, and pancreatic cancer. In particular, NTSR1 is overexpressed in at least 75% of pancreatic ductal adenocarcinomas. The aim of the present study was the development and evaluation of new 99mTc-labeled nonpeptide NTSR1-antagonists for SPECT imaging of NTSR-positive tumors. Methods: Multistep syntheses of NTSR1 antagonist derivatives were performed following our previously described procedure. Two different chelating strategies were applied for 99mTc radiolabeling to provide the [99mTc]Tc-HYNIC complex [99mTc]1 and the [99mTc]Tc-tricarbonyl complex [99mTc]2. Receptor binding assays were performed using hNTSR1-expressing CHO cells. Radiochemical yields (RCYs) were determined by radio-HPLC. For [99mTc]1 and [99mTc]2, log D7.4, plasma protein binding, stability in human plasma and serum, and cellular uptake in HT-29 cells were determined. Biodistribution studies and small animal SPECT studies were performed in HT-29 tumor-bearing nude mice. Results: The radiosynthesis of [99mTc]1 (log D7.4 = −0.27) and [99mTc]2 (log D7.4 = 1.00) was successfully performed with RCYs of 94–96% (decay-corrected). Both radioligands were stable in human serum and plasma, showed plasma protein binding of 72% ([99mTc]1) and 82% ([99mTc]2), and exhibited high and specific uptake in HT-29 cells. Biodistribution studies in HT-29 tumor-bearing mice showed a higher tumor accumulation of [99mTc]1 compared to [99mTc]2 (8.8 ± 3.4 %ID/g vs. 2.7 ± 0.2 %ID/g at 2 h p.i.). [99mTc]2 showed exceptionally high intestinal accumulation (49 ± 22 %ID/g at 1 h p.i.) and was therefore considered unfavorable. In the SPECT/CT imaging of HT-29 tumor xenografts, [99mTc]1 showed a higher NTSR1-specific tumor uptake than [99mTc]2 at all time points after tracer injection, with 12 ± 2.8 %ID/g for [99mTc]1 vs. 3.1 ± 1.1 %ID/g for [99mTc]2 at 4 h p.i. and adequate tumor-to-background ratios. Conclusions: In particular, the [99mTc]Tc-HYNIC ligand ([99mTc]1) showed promising preclinical results, being a potential candidate for SPECT imaging and, therefore, appropriate for translation into the clinic.

Effects of Adolescent Social Isolation on PFC’s β-Catenin Levels and Anxiety-Like Behaviors in Male and Female Rats: Study of the Role of Dopaminergic D2 Receptors

2025-05-27

Alejandrina Funes , A Ramirez , Cintia Konjuh +3 more

Unique Biased Agonism Profile of βCGRP on CGRP Family Receptors

2025-05-27

Grace Mennen , Ying Zhou , Madeleine M. Fletcher +6 more

α- and β-calcitonin gene-related peptides (αCGRP and βCGRP, respectively), together with adrenomedullin (AM) and AM2 are endogenous agonists of the CGRP family of receptors; CGRP receptor (CGRPR), AM1 receptor (AM1R), … α- and β-calcitonin gene-related peptides (αCGRP and βCGRP, respectively), together with adrenomedullin (AM) and AM2 are endogenous agonists of the CGRP family of receptors; CGRP receptor (CGRPR), AM1 receptor (AM1R), and AM2 receptor (AM2R). The high sequence homology and similar tissue distribution of αCGRP and βCGRP suggests they have overlapping physiological roles in pain pathways, inflammation, and metabolism, but recent data indicate potential differences in the signaling capabilities of these peptides. However, a comprehensive pharmacological characterization of βCGRP activity, compared to αCGRP, AM, and AM2 across the three CGRP family receptors, is lacking. In this study, we assessed proximal G protein coupling/activation, cognate second messenger production, regulatory protein recruitment and receptor trafficking induced by αCGRP, βCGRP, AM, and AM2 at the CGRPR, AM1R, and AM2R. Our findings revealed a distinct profile of transducer and regulatory protein engagement induced by βCGRP compared to αCGRP across these receptors. The identification of differences in pharmacological profiles for αCGRP and βCGRP indicates that they may have more distinct physiological roles than previously appreciated and may assist in distinguishing the roles of these two peptides for exploitation in targeted drug design.

Synergistic Crosstalk of PACAP and Notch Signaling Pathways in Bone Development

2025-05-26

Vince Szegeczki , Andrea Pálfi , Csaba Fillér +7 more

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide that plays significant regulatory roles in the differentiation of the central nervous system and peripheral organs. A lack of the neuropeptide can … Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide that plays significant regulatory roles in the differentiation of the central nervous system and peripheral organs. A lack of the neuropeptide can lead to abnormalities in long bone development. In callus formation, a possible signaling balance shift in PACAP KO mice has been demonstrated, but Notch signalization, with its potential connection with PACAP 1-38, has not been investigated in ossification. Our main goal was to show connections between PACAP and Notch signaling in osteogenesis. Notch signalization showed an elevation in the long bones of PACAP-gene-deficient mice, and it was also elevated during the PACAP 1-38 treatment of UMR-106 and MC3T3-E1 osteogenic cells. Moreover, the inhibition of Notch signaling was compensated by the addition of PACAP 1-38 in vitro. The inorganic and organic matrix production of UMR-106 cells was increased during PACAP 1-38 treatment under the inhibition of Notch signaling. As a possible common target, the expression and nuclear translocation of NFATc1 transcription factor was increased during the disturbance of PACAP and Notch signaling. Our results indicate a possible synergistic regulation during bone formation by PACAP and Notch signalization. The crosstalk between Notch and PACAP signaling pathways highlights the complexity of bone development and homeostasis.

Nociceptin/OrphaninFQ Receptor Modulates the Maturation of Adult-Born Neurons in the Mouse Dentate Gyrus Under Physiological Conditions and in a Chronic Stress Model

2025-05-26

Cathaline Robert , Flora D’Oliveira da Silva , Fabiola Seminara +7 more

Abstract Neurogenesis persists in the adult dentate gyrus (DG) of the hippocampus, playing a critical role in memory and stress adaptation. Dysregulation of this process is implicated in cognitive deficits … Abstract Neurogenesis persists in the adult dentate gyrus (DG) of the hippocampus, playing a critical role in memory and stress adaptation. Dysregulation of this process is implicated in cognitive deficits and depressive behaviors induced by chronic stress, while classical antidepressants are known to enhance neurogenesis. The Nociceptin/Orphanin FQ (N/OFQ) system, comprising N/OFQ and its NOP receptor, modulates memory and the stress response, yet its role in adult neurogenesis remains underexplored. Here, we investigated the impact of N/OFQ signaling on neurogenesis in the mouse DG using genetic and pharmacological approaches under basal and chronic stress conditions. In constitutive NOP receptor knockout (KO) mice, adult neurogenesis was only mildly altered, with subtle changes in neuronal maturation. However, spine density in 4-week-old adult-born DG neurons increased following conditional NOP Receptor KO in the DG. The increase was specific to stubby and thin spines, while mature mushroom spine density decreased. When NOP KO was restricted to newly born neurons, no significant differences were observed in spine density suggesting that the absence of NOP receptors in mature DG neurons influences the local environment to regulate spinogenesis in adult-born neurons indirectly. Finally, chronic corticosterone exposure impaired spinogenesis in immature neurons, and this was mitigated by systemic administration of a NOP antagonist. Our findings suggest that N/OFQ signaling indirectly regulates the maturation and connectivity of adult-born neurons through modulation of local and distal inputs. This regulation may contribute to the antidepressant and pro-cognitive effects of NOP receptor antagonists.