Biochemistry, Genetics and Molecular Biology › Molecular Biology

Ion channel regulation and function

Works Count: 95534

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Description

This cluster of papers explores the molecular mechanisms, structure, regulation, and physiological roles of ion channels, with a focus on voltage-gated potassium and calcium channels. It covers topics such as channel structure, membrane proteins, neuronal function, and cell signaling.

Keywords

Ion Channels; Voltage-Gated Channels; Calcium Channels; Potassium Channels; Channel Regulation; Membrane Proteins; Neuronal Function; Cell Signaling; Channel Structure; Physiological Roles

Inhibitory effect of a marine-sponge toxin, okadaic acid, on protein phosphatases. Specificity and kinetics

1988-11-15

Corinna Bialojan , Akira Takai

The inhibitory effect of a marine-sponge toxin, okadaic acid, was examined on type 1, type 2A, type 2B and type 2C protein phosphatases as well as on a polycation-modulated (PCM) … The inhibitory effect of a marine-sponge toxin, okadaic acid, was examined on type 1, type 2A, type 2B and type 2C protein phosphatases as well as on a polycation-modulated (PCM) phosphatase. Of the protein phosphatases examined, the catalytic subunit of type 2A phosphatase from rabbit skeletal muscle was most potently inhibited. For the phosphorylated myosin light-chain (PMLC) phosphatase activity of the enzyme, the concentration of okadaic acid required to obtain 50% inhibition (ID50) was about 1 nM. The PMLC phosphatase activities of type 1 and PCM phosphatase were also strongly inhibited (ID50 0.1-0.5 microM). The PMCL phosphatase activity of type 2B phosphatase (calcineurin) was inhibited to a lesser extent (ID50 4-5 microM). Similar results were obtained for the phosphorylase a phosphatase activity of type 1 and PCM phosphatases and for the p-nitrophenyl phosphate phosphatase activity of calcineurin. The following phosphatases were not affected by up to 10 microM-okadaic acid: type 2C phosphatase, phosphotyrosyl phosphatase, inositol 1,4,5-trisphosphate phosphatase, acid phosphatases and alkaline phosphatases. Thus okadaic acid had a relatively high specificity for type 2A, type 1 and PCM phosphatases. Kinetic studies showed that okadaic acid acts as a non-competitive or mixed inhibitor on the okadaic acid-sensitive enzymes.

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Calcium - a life and death signal

1998-10-01

Michael J. Berridge , Martin D. Bootman , Peter Lipp

Relaxation of Arterial Smooth Muscle by Calcium Sparks

1995-10-27

Mark T. Nelson , Heping Cheng , Michael Rubart +4 more

Local increases in intracellular calcium ion concentration ([Ca 2+ ] i ) resulting from activation of the ryanodine-sensitive calcium-release channel in the sarcoplasmic reticulum (SR) of smooth muscle cause arterial … Local increases in intracellular calcium ion concentration ([Ca 2+ ] i ) resulting from activation of the ryanodine-sensitive calcium-release channel in the sarcoplasmic reticulum (SR) of smooth muscle cause arterial dilation. Ryanodine-sensitive, spontaneous local increases in [Ca 2+ ] i (Ca 2+ sparks) from the SR were observed just under the surface membrane of single smooth muscle cells from myogenic cerebral arteries. Ryanodine and thapsigargin inhibited Ca 2+ sparks and Ca 2+ -dependent potassium (K Ca ) currents, suggesting that Ca 2+ sparks activate K Ca channels. Furthermore, K Ca channels activated by Ca 2+ sparks appeared to hyperpolarize and dilate pressurized myogenic arteries because ryanodine and thapsigargin depolarized and constricted these arteries to an extent similar to that produced by blockers of K Ca channels. Ca 2+ sparks indirectly cause vasodilation through activation of K Ca channels, but have little direct effect on spatially averaged [Ca 2+ ] i , which regulates contraction.

Biophysical and Molecular Mechanisms of Shaker Potassium Channel Inactivation

1990-10-26

Toshinori Hoshi , William N. Zagotta , Richard W. Aldrich

The potassium channels encoded by the Drosophila Shaker gene activate and inactivate rapidly when the membrane potential becomes more positive. Site-directed mutagenesis and single-channel patch-clamp recording were used to explore … The potassium channels encoded by the Drosophila Shaker gene activate and inactivate rapidly when the membrane potential becomes more positive. Site-directed mutagenesis and single-channel patch-clamp recording were used to explore the molecular transitions that underlie inactivation in Shaker potassium channels expressed in Xenopus oocytes. A region near the amino terminus with an important role in inactivation has now been identified. The results suggest a model where this region forms a cytoplasmic domain that interacts with the open channel to cause inactivation.

Atomic structure of a voltage-dependent K+ channel in a lipid membrane-like environment

2007-11-15

Stephen B. Long , Xiao Tao , Ernest B. Campbell +1 more

From Ionic Currents to Molecular Mechanisms

2000-04-01

William A. Catterall

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Muscarinic activation of ionic currents measured by a new whole-cell recording method.

1988-08-01

R Horn , Alain Marty

A new method is described as an alternative to whole-cell recording in order to prevent "wash-out" of the muscarinic response to acetylcholine (ACh) in rat lacrimal gland cells. The membrane … A new method is described as an alternative to whole-cell recording in order to prevent "wash-out" of the muscarinic response to acetylcholine (ACh) in rat lacrimal gland cells. The membrane of a cell-attached patch is permeabilized by nystatin in the patch pipette, thus providing electrical continuity between the pipette and the cytoplasm of the cell without the loss or alteration of cytoplasmic compounds necessary for the maintenance of the response to ACh. With normal whole-cell recording in these cells, the response to ACh, seen as the activation of Ca-activated K and Cl currents, lasts for approximately 5 min. With the nystatin method, the response is not diminished after 1 h. Nystatin, applied extracellularly, is shown to cause a rapid and reversible increase of membrane conductance to cations. In the absence of wash-out, we were able to obtain dose-response curves for the effect of ACh on Ca-activated K currents. An increase of [ACh] caused an increase in the K current, with apparent saturation at concentrations above approximately 1 microM ACh. The delay between ACh application and the activation of K current was inversely related to [ACh] and reached a minimum value of 0.7-1.0 s at high [ACh].

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Decreased Catecholamine Sensitivity and β-Adrenergic-Receptor Density in Failing Human Hearts

1982-07-22

Michael R. Bristow , Robert Ginsburg , Wayne Minobe +6 more

To identify the role of the myocardial β-adrenergic pathway in congestive heart failure, we examined β-adrenergic-receptor density, adenylate cyclase and creatine kinase activities, muscle contraction in vitro, and myocardial contractile … To identify the role of the myocardial β-adrenergic pathway in congestive heart failure, we examined β-adrenergic-receptor density, adenylate cyclase and creatine kinase activities, muscle contraction in vitro, and myocardial contractile protein levels in the left ventricles of failing and normally functioning hearts from cardiac-transplant recipients or prospective donors. Eleven failing left ventricles had a 50 to 56 per cent reduction in β-receptor density, a 45 per cent reduction in maximal isoproterenol-mediated adenylate cyclase stimulation, and a 54 to 73 per cent reduction in maximal isoproterenol-stimulated muscle contraction, as compared with six normally functioning ventricles (P<0.05 for each comparison). In contrast, cytoplasmic creatine kinase activity, adenylate cyclase activities stimulated by fluoride ion and by histamine, histamine-stimulated muscle contraction, and levels of contractile protein were not different in the two groups (P>0.05). We conclude that in failing human hearts a decrease in β-receptor density leads to subsensitivity of the β-adrenergic pathway and decreased β-agonist-stimulated muscle contraction. Regulation of β-adrenergic receptors may be an important variable in cardiac failure. (N Engl J Med. 1982; 307:205–11.)

Magnesium gates glutamate-activated channels in mouse central neurones

1984-02-01

Linda M. Nowak , Pìotr Bregestovski , Philippe Ascher +2 more

Bell-shaped calcium-response curves of lns(l,4,5)P3- and calcium-gated channels from endoplasmic reticulum of cerebellum

1991-06-01

Ilya Bezprozvanny , J Watras , Barbara E. Ehrlich

Molecular Biology of Learning: Modulation of Transmitter Release

1982-10-29

Eric R. Kandel , James H. Schwartz

Until recently, it has been impossible to approach learning with the techniques of cell biology. During the past several years, elementary forms of learning have been analyzed in higher invertebrates. … Until recently, it has been impossible to approach learning with the techniques of cell biology. During the past several years, elementary forms of learning have been analyzed in higher invertebrates. Their nervous systems allow the experimental study of behavioral, neurophysiological, morphological, biochemical, and genetic components of the functional (plastic) changes underlying learning. In this review, we focus primarily on short-term sensitization of the gill and siphon reflex in the marine mollusk, Aplysia californica . Analyses of this form of learning provide direct evidence that protein phosphorylation dependent on cyclic adenosine monophosphate can modulate synaptic action. These studies also suggest how the molecular mechanisms for this short-term form of synaptic plasticity can be extended to explain both long-term memory and classical conditioning.

A study of the ‘desensitization’ produced by acetylcholine at the motor end‐plate

1957-08-29

B. Katz , S. Thesleff

Cloning and characterization of an extracellular Ca2+-sensing receptor from bovine parathyroid

1993-12-01

Edward M. Brown , Gerardo Gamba , Daniela Riccardi +7 more

Dopamine Receptor Binding Predicts Clinical and Pharmacological Potencies of Antischizophrenic Drugs

1976-04-30

Ian Creese , David R. Burt , Solomon H. Snyder

Tritiated haloperidol and tritiated dopamine label postsynaptic dopamine receptors in mammalian brain. Clinical potencies of butyrophenones, phenothiazines, and related drugs correlate closely with their ability to inhibit tritiated haloperidol binding. … Tritiated haloperidol and tritiated dopamine label postsynaptic dopamine receptors in mammalian brain. Clinical potencies of butyrophenones, phenothiazines, and related drugs correlate closely with their ability to inhibit tritiated haloperidol binding. These binding methods provide a simple in vitro means for evaluating new drugs as potential antischizophrenic agents.

Depletion of intracellular calcium stores activates a calcium current in mast cells

1992-01-01

Markus Hoth , Reinhold Penner

X-ray structure of a voltage-dependent K+ channel

2003-04-30

Youxing Jiang , Alice Lee , Jiayun Chen +4 more

Primary structure of the receptor for calcium channel blockers from skeletal muscle

1987-07-01

Tsutomu Tanabe , Hiroshi Takeshima , Atsushi Mikami +7 more

Store depletion and calcium influx

1997-10-01

Anant B. Parekh , Reinhold Penner

Calcium influx in nonexcitable cells regulates such diverse processes as exocytosis, contraction, enzyme control, gene regulation, cell proliferation, and apoptosis. The dominant Ca2+ entry pathway in these cells is the … Calcium influx in nonexcitable cells regulates such diverse processes as exocytosis, contraction, enzyme control, gene regulation, cell proliferation, and apoptosis. The dominant Ca2+ entry pathway in these cells is the store-operated one, in which Ca2+ entry is governed by the Ca2+ content of the agonist-sensitive intracellular Ca2+ stores. Only recently has a Ca2+ current been described that is activated by store depletion. The properties of this new current, called Ca2+ release-activated Ca2+ current (ICRAC), have been investigated in detail using the patch-clamp technique. Despite intense research, the nature of the signal that couples Ca2+ store content to the Ca2+ channels in the plasma membrane has remained elusive. Although ICRAC appears to be the most effective and widespread influx pathway, other store-operated currents have also been observed. Although the Ca2+ release-activated Ca2+ channel has not yet been cloned, evidence continues to accumulate that the Drosophila trp gene might encode a store-operated Ca2+ channel. In this review, we describe the historical development of the field of Ca2+ signaling and the discovery of store-operated Ca2+ currents. We focus on the electrophysiological properties of the prototype store-operated current ICRAC, discuss the regulatory mechanisms that control it, and finally consider recent advances toward the identification of molecular mechanisms involved in this ubiquitous and important Ca2+ entry pathway.

Calcium Sparks: Elementary Events Underlying Excitation-Contraction Coupling in Heart Muscle

1993-10-29

Heping Cheng , W. Jonathan Lederer , Mark B. Cannell

Spontaneous local increases in the concentration of intracellular calcium, called "calcium sparks," were detected in quiescent rat heart cells with a laser scanning confocal microscope and the fluorescent calcium indicator … Spontaneous local increases in the concentration of intracellular calcium, called "calcium sparks," were detected in quiescent rat heart cells with a laser scanning confocal microscope and the fluorescent calcium indicator fluo-3. Estimates of calcium flux associated with the sparks suggest that calcium sparks result from spontaneous openings of single sarcoplasmic reticulum (SR) calcium-release channels, a finding supported by ryanodine-dependent changes of spark kinetics. At resting intracellular calcium concentrations, these SR calcium-release channels had a low rate of opening (∼0.0001 per second). An increase in the calcium content of the SR, however, was associated with a fourfold increase in opening rate and resulted in some sparks triggering propagating waves of increased intracellular calcium concentration. The calcium spark is the consequence of elementary events underlying excitation-contraction coupling and provides an explanation for both spontaneous and triggered changes in the intracellular calcium concentration in the mammalian heart.

Three types of neuronal calcium channel with different calcium agonist sensitivity

1985-08-01

Martha C. Nowycky , Aaron P. Fox , Richard W. Tsien

ATP-regulated K+ channels in cardiac muscle

1983-09-01

Akinori Noma

Nomenclature of Voltage-Gated Sodium Channels

2000-11-01

Alan L. Goldin , Robert L. Barchi , John H. Caldwell +7 more

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Multiple types of neuronal calcium channels and their selective modulation

1988-01-01

Richard W. Tsien , Diane Lipscombe , Daniel V. Madison +2 more

A model for receptor-regulated calcium entry

1986-02-01

James W. Putney

The action potential in mammalian central neurons

2007-05-19

Bruce P. Bean

Amiloride-sensitive epithelial Na+ channel is made of three homologous subunits

1994-02-01

Cecilia M. Canessa , Laurent Schild , Gary Buell +4 more

Voltage-Gated Calcium Channels

2011-07-11

William A. Catterall

William A. Catterall Department of Pharmacology, University of Washington, Seattle, Washington 98195-7280 Correspondence: wcatt{at}uw.edu William A. Catterall Department of Pharmacology, University of Washington, Seattle, Washington 98195-7280 Correspondence: wcatt{at}uw.edu

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Crystal structure and mechanism of a calcium-gated potassium channel

2002-05-01

Youxing Jiang , Alice Lee , Jiayun Chen +3 more

Spontaneous subthreshold activity at motor nerve endings

1952-05-28

P. Fatt , B. Katz

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The crystal structure of a voltage-gated sodium channel

2011-07-01

Jian Payandeh , Todd Scheuer , Ning Zheng +1 more

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Crystal structure of a bacterial homologue of Na+/Cl--dependent neurotransmitter transporters

2005-07-24

Atsuko Yamashita , Satinder K. Singh , Toshimitsu Kawate +2 more

Extracellular Calcium Sensing and Extracellular Calcium Signaling

2001-01-01

Edward M. Brown , John Macleod

The cloning of a G protein-coupled extracellular Ca 2+ (Ca o 2+ )-sensing receptor (CaR) has elucidated the molecular basis for many of the previously recognized effects of Ca o … The cloning of a G protein-coupled extracellular Ca 2+ (Ca o 2+ )-sensing receptor (CaR) has elucidated the molecular basis for many of the previously recognized effects of Ca o 2+ on tissues that maintain systemic Ca o 2+ homeostasis, especially parathyroid chief cells and several cells in the kidney. The availability of the cloned CaR enabled the development of DNA and antibody probes for identifying the CaR's mRNA and protein, respectively, within these and other tissues. It also permitted the identification of human diseases resulting from inactivating or activating mutations of the CaR gene and the subsequent generation of mice with targeted disruption of the CaR gene. The characteristic alterations in parathyroid and renal function in these patients and in the mice with “knockout” of the CaR gene have provided valuable information on the CaR's physiological roles in these tissues participating in mineral ion homeostasis. Nevertheless, relatively little is known about how the CaR regulates other tissues involved in systemic Ca o 2+ homeostasis, particularly bone and intestine. Moreover, there is evidence that additional Ca o 2+ sensors may exist in bone cells that mediate some or even all of the known effects of Ca o 2+ on these cells. Even more remains to be learned about the CaR's function in the rapidly growing list of cells that express it but are uninvolved in systemic Ca o 2+ metabolism. Available data suggest that the receptor serves numerous roles outside of systemic mineral ion homeostasis, ranging from the regulation of hormonal secretion and the activities of various ion channels to the longer term control of gene expression, programmed cell death (apoptosis), and cellular proliferation. In some cases, the CaR on these “nonhomeostatic” cells responds to local changes in Ca o 2+ taking place within compartments of the extracellular fluid (ECF) that communicate with the outside environment (e.g., the gastrointestinal tract). In others, localized changes in Ca o 2+ within the ECF can originate from several mechanisms, including fluxes of calcium ions into or out of cellular or extracellular stores or across epithelium that absorb or secrete Ca 2+ . In any event, the CaR and other receptors/sensors for Ca o 2+ and probably for other extracellular ions represent versatile regulators of numerous cellular functions and may serve as important therapeutic targets.

An SCN9A channelopathy causes congenital inability to experience pain

2006-12-01

James J. Cox , Frank Reimann , Adeline K. Nicholas +7 more

Structure and Regulation of Voltage-Gated Ca2+ Channels

2000-11-01

William A. Catterall

▪ Abstract Voltage-gated Ca 2+ channels mediate Ca 2+ entry into cells in response to membrane depolarization. Electrophysiological studies reveal different Ca 2+ currents designated L-, N-, P-, Q-, R-, … ▪ Abstract Voltage-gated Ca 2+ channels mediate Ca 2+ entry into cells in response to membrane depolarization. Electrophysiological studies reveal different Ca 2+ currents designated L-, N-, P-, Q-, R-, and T-type. The high-voltage-activated Ca 2+ channels that have been characterized biochemically are complexes of a pore-forming α 1 subunit of ∼190–250 kDa; a transmembrane, disulfide-linked complex of α 2 and δ subunits; an intracellular β subunit; and in some cases a transmembrane γ subunit. Ten α 1 subunits, four α 2 δ complexes, four β subunits, and two γ subunits are known. The Ca v 1 family of α 1 subunits conduct L-type Ca 2+ currents, which initiate muscle contraction, endocrine secretion, and gene transcription, and are regulated primarily by second messenger-activated protein phosphorylation pathways. The Ca v 2 family of α 1 subunits conduct N-type, P/Q-type, and R-type Ca 2+ currents, which initiate rapid synaptic transmission and are regulated primarily by direct interaction with G proteins and SNARE proteins and secondarily by protein phosphorylation. The Ca v 3 family of α 1 subunits conduct T-type Ca 2+ currents, which are activated and inactivated more rapidly and at more negative membrane potentials than other Ca 2+ current types. The distinct structures and patterns of regulation of these three families of Ca 2+ channels provide a flexible array of Ca 2+ entry pathways in response to changes in membrane potential and a range of possibilities for regulation of Ca 2+ entry by second messenger pathways and interacting proteins.

Chemistry of ion coordination and hydration revealed by a K+ channel–Fab complex at 2.0 Å resolution

2001-11-01

Yufeng Zhou , João H. Morais‐Cabral , Amelia Kaufman +1 more

Store-Operated Calcium Channels

2005-03-23

Anant B. Parekh , James W. Putney

In electrically nonexcitable cells, Ca(2+) influx is essential for regulating a host of kinetically distinct processes involving exocytosis, enzyme control, gene regulation, cell growth and proliferation, and apoptosis. The major … In electrically nonexcitable cells, Ca(2+) influx is essential for regulating a host of kinetically distinct processes involving exocytosis, enzyme control, gene regulation, cell growth and proliferation, and apoptosis. The major Ca(2+) entry pathway in these cells is the store-operated one, in which the emptying of intracellular Ca(2+) stores activates Ca(2+) influx (store-operated Ca(2+) entry, or capacitative Ca(2+) entry). Several biophysically distinct store-operated currents have been reported, but the best characterized is the Ca(2+) release-activated Ca(2+) current, I(CRAC). Although it was initially considered to function only in nonexcitable cells, growing evidence now points towards a central role for I(CRAC)-like currents in excitable cells too. In spite of intense research, the signal that relays the store Ca(2+) content to CRAC channels in the plasma membrane, as well as the molecular identity of the Ca(2+) sensor within the stores, remains elusive. Resolution of these issues would be greatly helped by the identification of the CRAC channel gene. In some systems, evidence suggests that store-operated channels might be related to TRP homologs, although no consensus has yet been reached. Better understood are mechanisms that inactivate store-operated entry and hence control the overall duration of Ca(2+) entry. Recent work has revealed a central role for mitochondria in the regulation of I(CRAC), and this is particularly prominent under physiological conditions. I(CRAC) therefore represents a dynamic interplay between endoplasmic reticulum, mitochondria, and plasma membrane. In this review, we describe the key electrophysiological features of I(CRAC) and other store-operated Ca(2+) currents and how they are regulated, and we consider recent advances that have shed insight into the molecular mechanisms involved in this ubiquitous and vital Ca(2+) entry pathway.

CaV1.2 Calcium Channel Dysfunction Causes a Multisystem Disorder Including Arrhythmia and Autism

2004-10-01

Igor Splawski , Katherine W. Timothy , Leah M. Sharpe +7 more

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The Structure of the Potassium Channel: Molecular Basis of K + Conduction and Selectivity

1998-04-03

D. Doyle , João H. Morais‐Cabral , Richard A. Pfuetzner +5 more

The potassium channel from Streptomyces lividans is an integral membrane protein with sequence similarity to all known K + channels, particularly in the pore region. X-ray analysis with data to … The potassium channel from Streptomyces lividans is an integral membrane protein with sequence similarity to all known K + channels, particularly in the pore region. X-ray analysis with data to 3.2 angstroms reveals that four identical subunits create an inverted teepee, or cone, cradling the selectivity filter of the pore in its outer end. The narrow selectivity filter is only 12 angstroms long, whereas the remainder of the pore is wider and lined with hydrophobic amino acids. A large water-filled cavity and helix dipoles are positioned so as to overcome electrostatic destabilization of an ion in the pore at the center of the bilayer. Main chain carbonyl oxygen atoms from the K + channel signature sequence line the selectivity filter, which is held open by structural constraints to coordinate K + ions but not smaller Na + ions. The selectivity filter contains two K + ions about 7.5 angstroms apart. This configuration promotes ion conduction by exploiting electrostatic repulsive forces to overcome attractive forces between K + ions and the selectivity filter. The architecture of the pore establishes the physical principles underlying selective K + conduction.

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Crystal structure of the calcium pump of sarcoplasmic reticulum at 2.6 Å resolution

2000-06-01

Chikashi Toyoshima , Masayoshi Nakasako , H. Nomura +1 more

International Union of Pharmacology. XLVII. Nomenclature and Structure-Function Relationships of Voltage-Gated Sodium Channels

2005-12-01

William A. Catterall , Alan L. Goldin , Stephen G. Waxman

The family of voltage-gated sodium channels initiates action potentials in all types of excitable cells. Nine members of the voltage-gated sodium channel family have been characterized in mammals, and a … The family of voltage-gated sodium channels initiates action potentials in all types of excitable cells. Nine members of the voltage-gated sodium channel family have been characterized in mammals, and a 10th member has been recognized as a related protein. These distinct sodium channels have similar structural and functional properties, but they initiate action potentials in different cell types and have distinct regulatory and pharmacological properties. This article presents the molecular relationships and physiological roles of these sodium channel proteins and provides comprehensive information on their molecular, genetic, physiological, and pharmacological properties.

Inwardly Rectifying Potassium Channels: Their Structure, Function, and Physiological Roles

2010-01-01

Hiroshi Hibino , Atsushi Inanobe , Kazuharu Furutani +3 more

Inwardly rectifying K(+) (Kir) channels allow K(+) to move more easily into rather than out of the cell. They have diverse physiological functions depending on their type and their location. … Inwardly rectifying K(+) (Kir) channels allow K(+) to move more easily into rather than out of the cell. They have diverse physiological functions depending on their type and their location. There are seven Kir channel subfamilies that can be classified into four functional groups: classical Kir channels (Kir2.x) are constitutively active, G protein-gated Kir channels (Kir3.x) are regulated by G protein-coupled receptors, ATP-sensitive K(+) channels (Kir6.x) are tightly linked to cellular metabolism, and K(+) transport channels (Kir1.x, Kir4.x, Kir5.x, and Kir7.x). Inward rectification results from pore block by intracellular substances such as Mg(2+) and polyamines. Kir channel activity can be modulated by ions, phospholipids, and binding proteins. The basic building block of a Kir channel is made up of two transmembrane helices with cytoplasmic NH(2) and COOH termini and an extracellular loop which folds back to form the pore-lining ion selectivity filter. In vivo, functional Kir channels are composed of four such subunits which are either homo- or heterotetramers. Gene targeting and genetic analysis have linked Kir channel dysfunction to diverse pathologies. The crystal structure of different Kir channels is opening the way to understanding the structure-function relationships of this simple but diverse ion channel family.

X-ray structure of a ClC chloride channel at 3.0 Å reveals the molecular basis of anion selectivity

2002-01-01

Raimund Dutzler , Ernest B. Campbell , Martine Cadène +2 more

Crystal Structure of a Mammalian Voltage-Dependent Shaker Family K + Channel

2005-07-08

Stephen B. Long , Ernest B. Campbell , Roderick MacKinnon

Voltage-dependent potassium ion (K + ) channels (Kv channels) conduct K + ions across the cell membrane in response to changes in the membrane voltage, thereby regulating neuronal excitability by … Voltage-dependent potassium ion (K + ) channels (Kv channels) conduct K + ions across the cell membrane in response to changes in the membrane voltage, thereby regulating neuronal excitability by modulating the shape and frequency of action potentials. Here we report the crystal structure, at a resolution of 2.9 angstroms, of a mammalian Kv channel, Kv1.2, which is a member of the Shaker K + channel family. This structure is in complex with an oxido-reductase β subunit of the kind that can regulate mammalian Kv channels in their native cell environment. The activation gate of the pore is open. Large side portals communicate between the pore and the cytoplasm. Electrostatic properties of the side portals and positions of the T1 domain and β subunit are consistent with electrophysiological studies of inactivation gating and with the possibility of K + channel regulation by the β subunit.

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

2003-01-01

Edward Perez‐Reyes

T-type Ca2+ channels were originally called low-voltage-activated (LVA) channels because they can be activated by small depolarizations of the plasma membrane. In many neurons Ca2+ influx through LVA channels triggers … T-type Ca2+ channels were originally called low-voltage-activated (LVA) channels because they can be activated by small depolarizations of the plasma membrane. In many neurons Ca2+ influx through LVA channels triggers low-threshold spikes, which in turn triggers a burst of action potentials mediated by Na+ channels. Burst firing is thought to play an important role in the synchronized activity of the thalamus observed in absence epilepsy, but may also underlie a wider range of thalamocortical dysrhythmias. In addition to a pacemaker role, Ca2+ entry via T-type channels can directly regulate intracellular Ca2+ concentrations, which is an important second messenger for a variety of cellular processes. Molecular cloning revealed the existence of three T-type channel genes. The deduced amino acid sequence shows a similar four-repeat structure to that found in high-voltage-activated (HVA) Ca2+ channels, and Na+ channels, indicating that they are evolutionarily related. Hence, the alpha1-subunits of T-type channels are now designated Cav3. Although mRNAs for all three Cav3 subtypes are expressed in brain, they vary in terms of their peripheral expression, with Cav3.2 showing the widest expression. The electrophysiological activities of recombinant Cav3 channels are very similar to native T-type currents and can be differentiated from HVA channels by their activation at lower voltages, faster inactivation, slower deactivation, and smaller conductance of Ba2+. The Cav3 subtypes can be differentiated by their kinetics and sensitivity to block by Ni2+. The goal of this review is to provide a comprehensive description of T-type currents, their distribution, regulation, pharmacology, and cloning.

Calcium-induced release of calcium from the cardiac sarcoplasmic reticulum

1983-07-01

A Fabiato

The hypothesis of a Ca2+-induced Ca2+ release (CICR) from the sarcoplasmic reticulum (SR) is supported by experiments done in skinned cardiac cells (sarcolemma removed by microdissection). According to this hypothesis, … The hypothesis of a Ca2+-induced Ca2+ release (CICR) from the sarcoplasmic reticulum (SR) is supported by experiments done in skinned cardiac cells (sarcolemma removed by microdissection). According to this hypothesis, the transsarcolemmal Ca2+ influx does not activate the myofilaments directly but through the induction of a Ca2+ release from the SR. The stimulus gating CICR is not a small change in free Ca2+ concentration (delta[free Ca2+]) outside the SR but a function of the rate of this change (delta[free Ca2+/delta t]). The initial relatively fast component of the transsarcolemmal Ca2+ current would trigger Ca2+ release; the subsequent slow component, perhaps corresponding to noninactivating Ca2+ channels, would load the SR with an amount of Ca2+ available for release during subsequent beats. Inactivation of CICR is caused by the large increase of [free Ca2+] outside the SR resulting from Ca2+ release, which inhibits further release. This negative feedback helps to explain that CICR is not all or none. During relaxation the Ca2+ reaccumulation in the SR is backed up by the Ca2+ efflux across the sarcolemma through Na+-Ca2+ exchange and the sarcolemmal Ca2+ pump. Computations of the Ca2+ buffering in the mammalian ventricular cell and of the systolic transsarcolemmal Ca2+ influx do not support the alternative hypothesis that this influx of Ca2+ is large enough to activate the myofilaments directly. Yet the hypothesis of a CICR can be challenged because of many problems and uncertainties related to the preparations and methods used for skinned cardiac cell experiments.

Sodium/Calcium Exchange: Its Physiological Implications

1999-07-01

Mordecai P. Blaustein , W. Jonathan Lederer

The Na+/Ca2+ exchanger, an ion transport protein, is expressed in the plasma membrane (PM) of virtually all animal cells. It extrudes Ca2+ in parallel with the PM ATP-driven Ca2+ pump. … The Na+/Ca2+ exchanger, an ion transport protein, is expressed in the plasma membrane (PM) of virtually all animal cells. It extrudes Ca2+ in parallel with the PM ATP-driven Ca2+ pump. As a reversible transporter, it also mediates Ca2+ entry in parallel with various ion channels. The energy for net Ca2+ transport by the Na+/Ca2+ exchanger and its direction depend on the Na+, Ca2+, and K+ gradients across the PM, the membrane potential, and the transport stoichiometry. In most cells, three Na+ are exchanged for one Ca2+. In vertebrate photoreceptors, some neurons, and certain other cells, K+ is transported in the same direction as Ca2+, with a coupling ratio of four Na+ to one Ca2+ plus one K+. The exchanger kinetics are affected by nontransported Ca2+, Na+, protons, ATP, and diverse other modulators. Five genes that code for the exchangers have been identified in mammals: three in the Na+/Ca2+ exchanger family (NCX1, NCX2, and NCX3) and two in the Na+/Ca2+ plus K+ family (NCKX1 and NCKX2). Genes homologous to NCX1 have been identified in frog, squid, lobster, and Drosophila. In mammals, alternatively spliced variants of NCX1 have been identified; dominant expression of these variants is cell type specific, which suggests that the variations are involved in targeting and/or functional differences. In cardiac myocytes, and probably other cell types, the exchanger serves a housekeeping role by maintaining a low intracellular Ca2+ concentration; its possible role in cardiac excitation-contraction coupling is controversial. Cellular increases in Na+ concentration lead to increases in Ca2+ concentration mediated by the Na+/Ca2+ exchanger; this is important in the therapeutic action of cardiotonic steroids like digitalis. Similarly, alterations of Na+ and Ca2+ apparently modulate basolateral K+ conductance in some epithelia, signaling in some special sense organs (e.g., photoreceptors and olfactory receptors) and Ca2+-dependent secretion in neurons and in many secretory cells. The juxtaposition of PM and sarco(endo)plasmic reticulum membranes may permit the PM Na+/Ca2+ exchanger to regulate sarco(endo)plasmic reticulum Ca2+ stores and influence cellular Ca2+ signaling.

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Capacitative calcium entry revisited

1990-11-01

James W. Putney

The influence of some cations on an adenosine triphosphatase from peripheral nerves

1957-01-01

J.C. Skou

Calcium signaling

1995-01-01

David E. Clapham

Ion Channels/Excitable Membranes

2006-01-01

Heinrich Terlau , Frank Kirchhoff

Regulation of Kv7 Channel Function in Rat Bladder by <scp>ERα</scp> and <scp>GPER1</scp> Estrogen Receptors

2025-06-24

Zena Wehbe , Efthymia Papaevangelou , Sue Lynn Lau +2 more | The FASEB Journal

ABSTRACT This study investigated the sex and oestrous‐stage dependent effects on voltage‐gated potassium channels encoded by KCNQ genes (Kv7) channels in the rat bladder, focusing on the roles of different … ABSTRACT This study investigated the sex and oestrous‐stage dependent effects on voltage‐gated potassium channels encoded by KCNQ genes (Kv7) channels in the rat bladder, focusing on the roles of different estrogen receptors (ERs). We hypothesized that ERα and G‐protein‐coupled estrogen receptor (GPER1) play distinct roles in modulating Kv7.4 and Kv7.5 channel functionality and localization. Using bladder tissues from male and female Wistar rats at different oestrous stages, we performed myography, RT‐qPCR, immunocytochemistry, and western blot analyses. Our results showed that ML213, a Kv7.2–7.5 activator, was more effective in male bladders, correlating with higher membrane localization of Kv7.4 and Kv7.5. In contrast, female rats in the proestrous and oestrous stages exhibited reduced sensitivity to ML213, associated with decreased Kv7.5 membrane abundance. In this group, ERα attenuated both the Kv7 functional response to ML213 and the membrane localization of Kv7.5, whereas GPER1 was associated with reducing the membrane abundance of the channel without affecting functionality. In diestrous and metestrous rat bladders, ERα was not active in baseline conditions. Instead, GPER1 induced a removal of Kv7.5 from the membrane, without exerting any effect on the Kv7 functional response to ML213. These findings highlight a complex interplay between sex hormones and ERs in bladder smooth muscle cells, offering insights into sex‐specific differences in bladder function and potential therapeutic targets for bladder disorders.

Transient worsening of thyrotoxic myopathy following methimazole and metoprolol initiation in a 12-year-old girl: a case report and literature review

2025-06-24

Y Onishi , Shinji Higuchi , K Iwata +3 more | Journal of Pediatric Endocrinology and Metabolism

Abstract Objectives Thyrotoxic myopathy (TM) is a muscle disorder associated with hyperthyroidism. Although TM is common in adults, its incidence in children is unknown due to the limited number of … Abstract Objectives Thyrotoxic myopathy (TM) is a muscle disorder associated with hyperthyroidism. Although TM is common in adults, its incidence in children is unknown due to the limited number of reports. TM usually improves with the treatment of hyperthyroidism. This is the first report of a patient with TM who experienced transient worsening of muscle weakness shortly after administration of methimazole (MMI) and metoprolol tartrate. Case Presentation A 12-year-old Japanese girl with Graves’ disease was administered MMI and metoprolol tartrate. Within 12 h of treatment initiation, the patient experienced difficulty in standing from a chair. Examination revealed proximal lower-limb weakness and reduced grip strength. Based on the patient’s clinical course and blood test results, thyrotoxic periodic paralysis, myasthenia gravis, or polymyositis were considered unlikely. While the side effects of MMI and metoprolol tartrate were also considered as differential diagnoses, her history revealed mild pre-existing lower limb muscle weakness for 2 months before treatment, suggesting that the side effects of the medication were unlikely. Given the clinical course, the worsening of TM was the most probable cause, and treatment was continued cautiously. Muscle weakness gradually improved over 3 months as her thyroid hormone levels normalized. Magnetic resonance imaging taken 1 month later revealed gluteus muscle atrophy, which resolved within 10 months. Conclusions TM may show transient worsening after MMI and metoprolol tartrate administration, requiring the evaluation of TM, drug side effects, and other possible causes before continuing treatment. This case highlights the importance of recognizing TM in pediatric patients.

Key challenges and recommendations for defining organelle membrane contact sites

2025-06-23

Tito Calì , Emmanuelle Bayer , Emily R. Eden +7 more | Nature Reviews Molecular Cell Biology

Two-pore domain potassium channel TREK-1 contributes to arachidonic acid-induced Ca2+ signaling in human fibroblast-like synovial cells

2025-06-23

Battulga Khaltar , Futoshi Toyoda , Kosuke Kumagai +7 more | Biochemistry and Biophysics Reports

Casein Kinase 2 Regulates the Intrinsic Activity of L-Type Calcium Currents in Cardiomyocytes

2025-06-23

Juan Zhao , Marlena Broszczak , Lucie Parent | International Journal of Molecular Sciences

Heart failure is associated with dysregulation in cellular Ca2+ that could involve sarcolemmal L-type Ca2+ currents (LTCCs). Building on previous observations showing that recombinant CaV1.2 channels are upregulated by phosphorylated … Heart failure is associated with dysregulation in cellular Ca2+ that could involve sarcolemmal L-type Ca2+ currents (LTCCs). Building on previous observations showing that recombinant CaV1.2 channels are upregulated by phosphorylated calmodulin (CaM) variants, the cellular mechanism(s) underlying this posttranslational modification was investigated in cultured cardiomyocytes. Whole-cell LTCCs decreased by ≈75% after silencing the gene coding for casein kinase 2 (CK2), a constitutively active kinase in cardiomyocytes, or after its pharmacological inhibition. The overexpression of the dominant negative phosphoresistant single, double T79A/S81A, or triple T79A/S81A/S101A CaM variants resulted in a similar inhibition. In contrast, the overexpression of CaM WT or its double T79D/S81D and triple T79D/S81D/S101D phosphomimetic variants curtailed the downregulation of LTCCs caused by CK2 partial knockdown, suggesting that CK2 is responsible for the posttranslational modification of these CaM target residues. Catecholamines, triggering the protein kinase A (PKA) cascade, partially rescued LTCCs treated with siRNA without or after the overexpression of either CaM WT or stimulating CaM phosphomimetic variants. More importantly, they thwarted the negative impact of the phosphoresistant CaM variants, altogether arguing that CK2 and PKA are acting in synergy to regulate the activity of LTCCs. We conclude that CK2-mediated phosphorylation processes exacerbate the Ca2+ load associated with heart failure.

Retraction of Deficient LRRC8A-dependent volume-regulated anion channel activity is associated with male infertility in mice

2025-06-22

Jianqiang Bao , Carlos J. Pérez , Jeesun Kim +7 more | JCI Insight

Protocol to monitor cardiovascular effects of triiodothyronine in tumor-bearing mice via non-invasive electrocardiogram recordings

2025-06-20

Silvia Anahi Valdés-Rives , Yijun Yang , Zeng-jie Yang | STAR Protocols

Novel co-occurrence of SLC26A4 and KCTD7 variants in a pediatric patient with syndromic hearing loss and myoclonic epilepsy

2025-06-20

Fakhreddin Shariatmadari , Ahmed Kamal , Arshia Mobini +5 more | Egyptian Journal of Medical Human Genetics

Abstract Background Syndromic hearing loss and progressive myoclonic epilepsy are distinct genetic disorders with well-established genes implicated. SLC26A4 is commonly associated with hearing loss, including Pendred syndrome, while KCTD7 is … Abstract Background Syndromic hearing loss and progressive myoclonic epilepsy are distinct genetic disorders with well-established genes implicated. SLC26A4 is commonly associated with hearing loss, including Pendred syndrome, while KCTD7 is linked to PME, characterized by intractable seizures, cognitive regression, and ataxia. The co-occurrence of these two conditions in a single patient has not been previously reported. Case presentation We describe a 2-year-old boy presenting with bilateral severe-to-profound hearing loss, progressive myoclonic epilepsy, and global developmental delay. Whole exome sequencing revealed homozygous pathogenic and uncertain variants in SLC26A4 (c.1337A > G, p.Gln446Arg) and KCTD7 (c.766G > A, p.Gly256Ser), respectively. This is the first reported case of a patient with dual pathogenic and VUS variants in these genes, presenting with a novel combined phenotype. The patient showed partial seizure control with a regimen of clobazam, levetiracetam, and ACTH therapy. Notably, his auditory responses improved following seizure management, suggesting a possible interaction between epilepsy and auditory function. Conclusion This case highlights the importance of comprehensive genetic evaluation in patients with overlapping neurodevelopmental disorders. The co-occurrence of SLC26A4 and KCTD7 variants suggests a potential novel phenotype requiring further investigation. Functional studies and long-term follow-up are needed to assess the pathogenicity of the KCTD7 variant and its clinical significance in progressive myoclonic epilepsy.

Lacosamide-Induced Downbeat Nystagmus

2025-06-18

Jamir Pitton Rissardo , Ana Letícia Fornari Caprara , Karandeep Singh Bhatti | Neurology India

Extracellular K+modulates the pore conformations of Cys-loop receptor anion channels

2025-06-17

Takushi Shimomura , Minoru Saitoe , Yoshihiro Kubo +1 more | bioRxiv (Cold Spring Harbor Laboratory)

K + is an essential cation for life, but no eukaryotic membrane protein with a modulatory site for extracellular K + has been discovered. Here, we report that a Cys-loop … K + is an essential cation for life, but no eukaryotic membrane protein with a modulatory site for extracellular K + has been discovered. Here, we report that a Cys-loop receptor, CG12344/DmAlka, expressed in the Drosophila nervous system, is selectively modulated by physiological concentration of extracellular K + . Structural prediction, electrophysiology and phylogenetic analysis of DmAlka revealed the extracellular K + binding site that mimics the hydrated chemical environment for K + , as observed in K + channel pore. Furthermore, we found that K + binding induces a previously unrecognized 'mode-switching', altering properties ranging from ligand sensitivity to ion selectivity. Notably, a human glycine receptor variant also exhibited similar mechanisms. Our study reveals a novel regulatory mechanism of Cys-loop receptors that directly links the extracellular K + signaling to Cl - conductance in animals.

Epac1 increases myosin regulatory light-chain phosphorylation, energetic cost of contraction, and susceptibility to heart failure

2025-06-17

Yoshiki Ohnuki , Kenji Suita , Misao Ishikawa +7 more | PLoS ONE

β-Adrenergic receptor (β-AR) stimulation of the heart, leading to increased cardiac output, is mediated by cyclic AMP (cAMP), which induces protein kinase A (PKA)-mediated phosphorylation of the myofilament proteins troponin … β-Adrenergic receptor (β-AR) stimulation of the heart, leading to increased cardiac output, is mediated by cyclic AMP (cAMP), which induces protein kinase A (PKA)-mediated phosphorylation of the myofilament proteins troponin I (TnI) and myosin binding protein-C (MyBP-C). The aim of this study was to investigate the contribution of the exchange protein activated by cAMP (Epac1), a PKA-independent cAMP effector, to the response of cardiac myofilaments to β-AR stimulation. The calcium sensitivity of force and ATPase activity, and the tension cost (ATPase activity/force) were significantly greater in skinned myocardium from transgenic mice specifically overexpressing Epac1 in the heart (Epac1TG) and wild-type (WT) mice treated with 8CPT-AM, an Epac-selective cAMP analogue, as compared with non-transgenic (NTG) or control mice, respectively. In addition, myosin regulatory light chain (RLC) phosphorylation was significantly greater in Epac1TG and WT mice treated with 8CPT-AM than in NTG or control mice via phospholipase C/phosphokinase C, without any change in the phosphorylation of TnI or MyBP-C. We also examined the effects of chronic β-AR stimulation on cardiac function in Epac1TG. The left ventricular ejection fraction was significantly decreased from baseline in both NTG and Epac1TG after isoproterenol infusion (60 mg/kg/day for 1 week), but the magnitude of the decrease was much greater in Epac1TG. Our results suggest that Epac1 activation might induce an imbalance between force-generating capacity and ATPase activity in skinned myocardium. This could increase oxygen consumption and the energetic cost of contraction in living myocardium under conditions of chronic β-AR stimulation, leading to the development of heart failure.

A robust platform for recombinant production of animal venom toxin modulators of ion channels

2025-06-17

Jose Enrique Gonzalez-Prada , Alexander Haworth , J. Browne +7 more | bioRxiv (Cold Spring Harbor Laboratory)

Background and Purpose: Peptide toxins isolated from animal venom are potent and selective modulators of ion channels, and promising therapeutic leads. Due to intricate disulphide bridge patterns, they are often … Background and Purpose: Peptide toxins isolated from animal venom are potent and selective modulators of ion channels, and promising therapeutic leads. Due to intricate disulphide bridge patterns, they are often challenging to produce in standard laboratory settings, which limits engineering approaches to manipulate their structure-function properties. Given the low cost, wide accessibility, and versatility of recombinant expression systems for protein production, we set out to establish a straightforward high-yield strategy across a broad panel of peptide toxins from snakes, spiders and scorpions. Experimental Approach: 13 toxin DNA sequences were genetically fused to the C-terminus of either bivalent or monovalent human IgG1 antibody fragment crystallisable (Fc) domain sequences and expressed recombinantly from mammalian Expi293F cells. Affinity-purified proteins were evaluated by SDS-PAGE and size-exclusion chromatography (SEC). Function was assessed by Ca2+ flux assays on CN21 cells, or whole-cell electrophysiology on human embryonic kidney (HEK293T) cells, Chinese hamster ovary (CHO) cells, or dorsal root ganglion (DRG) neurons. Immunocytochemistry using HEK293T cells and mouse DRG neurons assessed Fc-toxin fusion binding. Key Results: Monovalent Fc-toxin fusions consistently yielded 1-6 mg of pure, non-proteolytically cleaved protein from 20-70 ml cultures for several toxin types, including three-finger toxins from snakes, inhibitory cystine knot (ICK) toxins from spiders, and α-toxins from scorpions, substantially surpassing the performance of unfused toxins or bivalent Fc-toxin fusions which gave low or no yield. Snake toxins targeting nicotinic acetylcholine receptors retained high single digit nanomolar inhibitory potency. Spider and scorpion toxins targeting the voltage-gated Na+ channel Nav1.7 retained pharmacological function and selectivity across a panel of five Nav subtypes, albeit with reduced potencies that did not exceed ~70 nM. Conclusions and Implications: We present a strategy for straightforward robust production of pure, monodisperse, and functional animal venom-derived toxins. This lowers the barrier to toxin production in a standard laboratory setting for follow-on engineering purposes.

Pharmacological and electrophysiological characterization of the novel Kv7 channel inhibitor racecadotril in Parkinson's disease

2025-06-17

Bo Yang , Hui Liu , Shifan Zhang +7 more | Neuropharmacology

Mechanical stimulation induces electrical coupling via TNTs through calcium-dependent mechanisms in C2C12 cells

2025-06-14

Yanli Sun , Hucheng Zhao | Biochemical and Biophysical Research Communications

Modulation of voltage-gated sodium channels by a nanoencapsulated α-toxin from Aah scorpion venom in an experimental lung cancer model

2025-06-14

Rania Merzouagui , Amina Mendil-Ladjel , Fatah Chérifi +5 more | Toxin Reviews

Phenotypic variability and preserved cognition in a family with KCNA2-related developmental epileptic encephalopathy

2025-06-14

Arastoo Kaki , Maedeh Ganji , Mohammad Farid Mohammadi +5 more | Neurogenetics

Abstract PS4-03: Calcium Channel Blockers Enhance Efficacy of TROP2-ADC in Overcoming Resistance in Advanced Triple-Negative Breast Cancer

2025-06-13

Jieer Luo , Qun Lin , Yu Shi +4 more | Clinical Cancer Research

Abstract The TROP2-directed antibody-drug conjugate (TROP2-ADC) has been approved for treating advanced triple-negative breast cancer (TNBC) that has progressed after chemotherapy. Recent findings from the ASCENT trial indicated that sacituzumab … Abstract The TROP2-directed antibody-drug conjugate (TROP2-ADC) has been approved for treating advanced triple-negative breast cancer (TNBC) that has progressed after chemotherapy. Recent findings from the ASCENT trial indicated that sacituzumab govitecan (SG), compared with standard chemotherapy, significantly prolongs median progression-free survival and overall survival in patients with advanced or refractory TNBC, reducing the risk of disease progression by 59% and the risk of death by 52%. However, approximately 20% of patients exhibit primary resistance to SG, experiencing disease progression within 3 months. Therefore, exploring the molecular mechanisms underlying TROP2-ADC resistance is crucial for reversing drug resistance and improving the prognosis of patients with advanced TNBC. In this study, we retrospectively observed that advanced TNBC patients with hypertension who were co-treated with SG and nifedipine displayed better survival times compared to advanced TNBC patients without hypertension who were treated with SG alone. Based on these findings, we constructed TNBC patient-derived xenografts (PDXs) that were either sensitive or insensitive to TROP2-ADC. We found that combining calcium channel blockers (CCBs) with TROP2-ADC significantly improved anti-tumor efficacy and maintained a manageable safety profile in TROP2-ADC insensitive models, both in vivo and in vitro. High-throughput sequencing of TNBC patients treated with TROP2-ADC revealed that pathways related to vesicle trafficking, calcium ion binding, and cell membrane processes were highly enriched in resistant patients. Mechanistically, excess intracellular calcium activated PKC and PACSIN2, leading to increased caveolae-mediated endocytosis. This resulted in defective plasma membrane localization of TROP2, contributing to TROP2-ADC resistance. In conclusion, our results provide insight into the potential mechanisms of TROP2-ADC resistance and suggest that combining CCBs with TROP2-ADC may offer a new therapeutic strategy for patients resistant to TROP2-ADC. Citation Format: Jieer Luo, Qun Lin, Yu Shi, Zhuxi Duan, Jinpeng Luo, Xiaolin Fang, Chang Gong. Calcium Channel Blockers Enhance Efficacy of TROP2-ADC in Overcoming Resistance in Advanced Triple-Negative Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr PS4-03.

Biophysical characterization and ion transport with cell‐based and proteoliposome reconstitution assays of invertebrate K+‐Cl− cotransporters

2025-06-13

Satoshi Fudo , Marina Verkhovskaya , Coralie Di Scala +2 more | FEBS Open Bio

The cation‐chloride cotransporter (CCC) family includes ion symporters that cotransport monovalent cations and Cl − , playing a crucial role in controlling cytoplasmic ion content. K + ‐Cl − cotransporters … The cation‐chloride cotransporter (CCC) family includes ion symporters that cotransport monovalent cations and Cl − , playing a crucial role in controlling cytoplasmic ion content. K + ‐Cl − cotransporters (KCCs) facilitate the symport of ions across the plasma membrane. The CCCs participate in various physiological processes, such as transepithelial ion transport and regulation of cell volume. Among KCCs, KCC2 has unique and essential functions in the central nervous system. KCC from Drosophila melanogaster ( Dm KCC) is an ortholog of mammalian KCCs. Its critical role in neuronal transmission has been demonstrated. Also, the cnidarian Hydra vulgaris has a functional KCC ( Hv KCC). Comparative analyses of these transporters with vertebrate counterparts can provide insights into the mechanism of KCC ion transport, regulation, and evolution. Thus, here we purified Dm KCC and Hv KCC and characterized their biophysical properties using differential scanning fluorimetry and light scattering. We evaluated their functionality in cells and developed a method to study ion transport with flame photometry. Further, a fluorescence‐based assay for Dm KCC reconstituted into proteoliposomes was developed. The activity of Dm KCC was found to be dependent on Ca 2+ , which is reminiscent of some other chloride transport protein families and potentially important for the KCC protein family overall.

Treatment Outcomes of Topiramate and Levetiracetam for Generalized Tonic-Clonic Seizures Among Adults with Idiopathic Generalized Epilepsy

2025-06-13

| Journal of Pakistan Society of Internal Medicine.

Malignant Hyperthermia

2025-06-09

| Cambridge University Press eBooks

De novo missense variants of KCNA3, KCNA4, and KCNA6 cause early onset developmental epileptic encephalopathy

2025-06-05

Meng‐Han Tsai , Chia-Hua Lo , Yunhe Liu +7 more | Human Molecular Genetics

Abstract Shaker-type potassium channel genes (Kv1) have been linked to human epilepsies, including KCNA1 (Kv1.1), KCNA2 (Kv1.2), and more recently, KCNA3 (Kv1.3) and KCNA6 (Kv1.6). In this study, we report … Abstract Shaker-type potassium channel genes (Kv1) have been linked to human epilepsies, including KCNA1 (Kv1.1), KCNA2 (Kv1.2), and more recently, KCNA3 (Kv1.3) and KCNA6 (Kv1.6). In this study, we report three early-onset epilepsy cases with de novo missense mutations in Shaker-type channel genes, including Kv1.3, KCNA4 (Kv1.4), and Kv1.6, identified through whole exome sequencing trio study. The newly identified Kv1.3-V478M, Kv1.6-T421I, and Kv1.4-V558L mutations are located within the channel selectivity filter or S6 hinge, both critical for channel gating. These variants are in paralogous locations of previously reported pathogenic variant in KCNA2. These mutations do not significantly affect trafficking and plasma membrane localization of the Kv channels. In contrast, our patch-clamp analysis in a cell-based system reveals that all three mutations cause severe loss-of-function channel properties. Additionally, our Drosophila model highlights the detrimental effects of Kv1.3-V478M on neural circuit activity. Current findings suggest that, similar to Kv1.1, Kv1.2, and Kv1.3, both loss-of-function and gain-of-function mutations in Kv1.6 may contribute to the phenotypic variability in epilepsy severity. Our study also extends the list of potassium channel genes implicated in human epilepsy, introducing Kv1.4 as a novel epilepsy-related gene.

The ADCY1-mediated cAMP signaling pathway mediates functional effects of montelukast treatment in brain organoids

2025-06-05

Zhenhong Xu , Hongye Yan , Bo Wang +7 more | Cellular and Molecular Life Sciences

Kcnq (Kv7) channels exhibit frequency-dependent responses via partial inductor-like gating dynamics

2025-06-05

Yuta Eguchi , Yuki Kuwano , Satoshi Okada +2 more | Communications Biology

Current status, hotspots and frontiers of ion channel-related research in glioblastoma: a bibliometric analysis from 2005 to 2024

2025-06-04

Zefeng He , Jing Liu , Qianxu Jin +3 more | Frontiers in Oncology

Glioma is the most common primary tumor of the central nervous system, with glioblastoma being its predominant pathological type. In recent years, research has demonstrated that ion channels are intricately … Glioma is the most common primary tumor of the central nervous system, with glioblastoma being its predominant pathological type. In recent years, research has demonstrated that ion channels are intricately linked with numerous biological processes in tumor cells, including apoptosis and migration, among others. This study employs bibliometric analysis to systematically examine and synthesize the knowledge structure and research focal points in the field of glioblastoma ion channels. Publications related to ion channels in glioblastoma, published between January 1, 2005 and December 31, 2024, were retrieved from the Web of Science Core Collection (WoSCC). The dataset comprises 764 articles and 234 reviews. Utilize VOSviewer, CiteSpace, Bibliometrix, and Excel to conduct an in-depth analysis and visualization of scholarly contributions based on country, institution, journal, and author. Additionally, examine highly cited publications, references, and keywords. From 2005 to 2024, the number of publications in this field has shown a consistent annual increase. The University of Alabama and Cancer are among the leading institutions and journals. Sontheimer Harald, from the United States, is the most prolific author in this field. The analysis of highly cited publications and co-cited references indicates that the research background and foundation focus on elucidating the mechanisms by which ion channels influence the onset and progression of glioblastoma. Keyword analysis indicated that “tumor microenvironment” (burst strength: 4. 67), “Ca 2+ activated K + channel” (burst strength: 3. 98), and “chloride channels” (burst strength: 3. 59) have been the keywords exhibiting the highest burst intensity over the past two decades. The keywords that have emerged with higher frequency in the past five years include “tumor microenvironment” (burst strength: 4. 67), “receptor” (burst strength: 3. 11), and “channels” (burst strength: 3. 11). Research on ion channels in glioblastoma has emerged as a prominent and rapidly evolving field of interest. Previous studies have primarily focused on the examination of specific ion channels and their functionalities. However, recent keyword analysis highlights the necessity to explore the interaction between ion channels and the tumor microenvironment. Meanwhile by integrating single-cell spatial transcriptomics and nanoparticle technologies, we can significantly enhance the efficacy of ion channel-targeting therapies.

Anesthetic Considerations for Patients With Hypokalemic Periodic Paralysis Undergoing Ambulatory Surgery: A Case Report

2025-06-01

Ashwini Joshi , Caroline Andrew , L. Christine | A&A Practice

The perioperative management of patients with hypokalemic periodic paralysis is challenging due to the risk of postoperative muscle weakness. We describe a patient with hypokalemic periodic paralysis who presented for … The perioperative management of patients with hypokalemic periodic paralysis is challenging due to the risk of postoperative muscle weakness. We describe a patient with hypokalemic periodic paralysis who presented for wisdom teeth extraction. Our perioperative goals included minimizing exposure to weakness triggers such as hypokalemia, pain, anxiety, hypothermia, and neuromuscular blockade. The patient tolerated the procedure under deep sedation with intravenous agents, local anesthesia, and a natural airway with spontaneous ventilation. He experienced mild upper extremity weakness postoperatively, which resolved spontaneously. This case report highlights considerations relevant to anesthesia care for patients with hypokalemic periodic paralysis having ambulatory surgeries.

Stable expression of voltage-gated calcium channel mRNA in α2δ (CACNA2D) knockout mouse brains

2025-06-01

Stefanie M. Geisler , Larissa Traxler , Gerald J. Obermair | Neuroscience

Voltage-gated Ca2+ channels (VGCCs) regulate Ca2+ entry in healthy and diseased neurons, and their function is modulated by auxiliary α2δ subunits. Among the four α2δ isoforms, α2δ-1, α2δ-2, and α2δ-3 … Voltage-gated Ca2+ channels (VGCCs) regulate Ca2+ entry in healthy and diseased neurons, and their function is modulated by auxiliary α2δ subunits. Among the four α2δ isoforms, α2δ-1, α2δ-2, and α2δ-3 show overlapping expression in various brain regions, raising questions about their respective specific and redundant roles. Here, we investigated if the loss of α2δ isoforms affects mRNA expression of other VGCC α1, α2δ, and β subunits. Moreover, qPCR expression profiling in knockout conditions provides insights into potential compensatory mechanisms. To this end, we analyzed the expression of the high-VGCC complement, including seven α1, four β, and four α2δ subunit isoforms, in hippocampal and striatal tissues from α2δ single and α2δ-1/-3 double knockout mice. Our findings reveal that mRNA expression profiles of hippocampal and striatal tissues contain the entire set of neuronal high-VGCC subunits. Notably, α2δ-3 mRNA is the most abundant isoform in striatum and α2δ-1/-3 double knockout mice show increased amounts of mutant α2δ-3 mRNA reporter transcripts compared to α2δ-3 single knockout mice. These findings support a critical role of α2δ-3 in GABAergic striatal medium spiny neurons. Of note, mRNA expression levels of individual α1 and β isoforms were remarkably similar between α2δ single knockout and α2δ-1/-3 double knockout compared to control mice. Taken together, our study provides novel insights into the resilience of VGCC mRNA levels to disruptions of α2δ isoform expression, suggesting transcriptional stability of core calcium channel components comparable to housekeeping genes. However, this stability does not fully prevent physiological deficits, suggesting limited functional compensation at the transcript level.

Neuromuscular junction toxins

2025-06-01

Michael D. Randall , Ryan Feldman | Disease-a-Month

Malignant Hyperthermia and Genetic Variability: A Complex Interaction

2025-06-01

Marina Ayres Delgado , Geovana Torres de Souza , André Drumond +1 more | Anaesthesia Critical Care & Pain Medicine