ABSTRACT Voltage-gated calcium channels (VGCCs) are critical for Ca2+ influx into all types of excitable cells, but their exact function is still poorly understood. Recent reconstruction of homology models for all human VGCCs at atomic resolution provides the opportunity for a structure-based discussion of VGCC function and novel insights into the mechanisms underlying Ca2+ selective flux through these

ABSTRACT Voltage-gated Ca2+ channels are typically integrated in a complex network of protein-protein-interactions, also referred to as Ca2+ channel nanodomains. Amongst the neuronal CaV2 channel family, CaV2.2 is of particular importance due to its general role for signal transmission from the periphery to the central nervous system, but also due to its significance for pain perception. Thus, CaV2

ABSTRACT Cytosolic Ca2+ concentration ([Ca2+ ]) has an important role in spermatozoa and hence it regulates fertilization. In male germinal cells, there are indirect evidences that this ion could regulate physiological processes in spermatogenesis. Since little is known about Ca 2+ homeostasis in spermatogenic cells, in this work we propose a mathematical model that accounts for experimental [Ca2+

ABSTRACT Arabidopsis thaliana contains five tandem-pore domain potassium channels, TPK1-TPK5 and the related one-pore domain potassium channel, KCO3. Although KCO3 is unlikely to be an active channel, it still has a physiological role in plant cells. TPK2 is most similar to KCO3 and both are localized to the tonoplast. However, their function remains poorly understood. Here, taking advantage of the

ABSTRACT Mechanosensitive (MS) ion channels are widespread mechanisms for cellular mechanosensation that can be directly activated by increasing membrane tension. The well-studied MscS family of MS ion channels is found in bacteria, archaea, and plants. MscS-Like (MSL)1 is localized to the inner mitochondrial membrane of Arabidopsis thaliana, where it is required for normal mitochondrial responses

ABSTRACT Ca2+-induced Ca2+ release (CICR) from sarcoplasmic reticulum is a finely tuned process responsible for cardiac excitation and contraction. The ubiquitin–proteasome system (UPS) as a major degradative system plays a crucial role in the maintenance of Ca2+ homeostasis. The E3 component N-recognin (UBR) subfamily is a part of the UPS; however, the role of UBR in regulating cardiac CICR is unknown

The KCNH family comprises the ERG, EAG, and ELK voltage-activated, potassium-selective channels. Distinct from other K channels, KCNH channels contain unique structural domains, including a PAS (Per-Arnt-Sim) domain in the N-terminal region and a CNBHD (cyclic nucleotide-binding homology domain) in the C-terminal region. The intracellular PAS domains and CNBHDs interact directly and regulate some of

ABSTRACT The cardiac voltage-gated sodium channel Nav1.5 conducts the rapid inward sodium current crucial for cardiomyocyte excitability. Loss-of-function mutations in its gene SCN5A are linked to cardiac arrhythmias such as Brugada Syndrome (BrS). Several BrS-associated mutations in the Nav1.5 N-terminal domain (NTD) exert a dominant-negative effect (DNE) on wild-type channel function, for which mechanisms

ABSTRACT CACNA1 C, which codes for the Cav1.2 isoform of L-type Ca2+ channels (LTCCs), is a prominent risk gene in neuropsychiatric and neurodegenerative conditions. A role forLTCCs, and Cav1.2 in particular, in transcription-dependent late long-term potentiation (LTP) has long been known. Here, we report that elimination of Cav1.2 channels in glutamatergic neurons also impairs theta burst stimulation

ABSTRACT TRPC3 is a Ca2+-permeable cation channel commonly activated by the G-protein coupled receptors (GPCR) and mechanical distortion of the plasma membrane. TRPC3-mediated Ca2+ influx has been implicated in a variety of signaling processes in both excitable and non-excitable cells. Kidneys play a commanding role in maintaining whole-body homeostasis and setting blood pressure. TRPC3 is expressed

ABSTRACT The elevated intracellular Ca2+ and oxidative stress are well-reported mechanisms behind renal tubular epithelial injury initiated by various insults. Given that TRPV4 and connexin43 (Cx43) channels are activated by a wide range of stimuli and regulate both intracellular Ca2+ and redox status, we speculated an involvement of these channels in renal tubular cell injury. Here, we tested this

ABSTRACT Low voltage activated (ICa-LVA) calcium currents including Cav1.3 and T-type calcium current (ICa-T) have not been reported in adult human left ventricular myocytes (HLVMs). We tried to examine their existence and possible correlation with etiology and patient characteristics in a big number of human LVMs isolated from explanted terminally failing (F) hearts, failing hearts with left ventricular

ABSTRACT Calcium channels are involved in pathologies across all the major therapeutic areas involving the cardiac, neurological, metabolic, and respiratory systems. Although calcium channels have been the hotspot of multidisciplinary research for decades, the hotspots and frontier trends of calcium channel research have not been comprehensively analyzed by bibliometrics. Here, we collected scientific

ABSTRACT Sphingolipids regulate multiple cellular processes, including proliferation, autophagy, and apoptosis. Sphingosine kinases, the key enzymes in the metabolism of sphingolipids, are overexpressed in many cancers, making them important targets for the development of antitumor drugs. ABC294640 is a selective sphingosine kinase 2 (SK2) inhibitor that shows good antitumor activity in vitro. One

ABSTRACT The transient receptor potential melastatin-subfamily member 7 (TRPM7) is a ubiquitously expressed protein that contains both an ion channel and an active kinase. TRPM7 has involved in a variety of cellular functions and critically participates in various diseases mainly including cancer and neurodegenerative disorders. However, the theme trends and knowledge structures for TRPM7 have not

ABSTRACT The voltage-sensing phosphatase (VSP) is a unique protein that shows voltage-dependent phosphatase activity toward phosphoinositides. Recently, we reported that VSP is activated and generates polarized PtdIns(4,5)P2 distribution in sperm flagellum. Interestingly, such specialized PtdIns(4,5)P2 distribution appears to contribute to the activity of Slo3, a sperm-specific K+ channels. It has

ABSTRACT Myeloid differentiation protein 1 (MD1) is exerted an anti-arrhythmic effect in obese mice. Therefore, we sought to clarify whether MD1 can alter the electrophysiological remodeling of cardiac myocytes from obese mice by regulating voltage-gated potassium current and calcium current. MD1 knock-out (KO) and wild type (WT) mice were given a high-fat diet (HFD) for 20 weeks, starting at the age

Congenital hyperinsulinemic hypoglycemia is the most frequent cause of persistent and recurrent hypoglycemia in the first years of life and in many patients rare genetic variants can be identified. Recently a case of congenital hyperinsulinemic hypoglycemia and a severe neurodevelopmental syndrome due to a mutation in the voltage-gated Cav1.3 Ca2+ channel CACNA1D gene has been reported which required

The congenital long QT syndrome (LQTS) is a cardiac disorder characterized by a prolonged QT interval on the electrocardiogram and an increased susceptibility to ventricular arrhythmias and sudden cardiac death. A frequent cause for LQTS is mutations in the KCNH2 gene (also known as the human ether-a-go-go-related gene or hERG), which reduce or modulate the potassium current IKr and hence alter cardiac

Residue Thr1604 in the CaV1.2 channel is a Ca2+/calmodulin dependent protein kinase II (CaMKII) phosphorylation site, and its phosphorylation status maintains the basic activity of the channel. However, the role of CaV1.2 phosphorylation at Thr1604 in myocardial hypertrophy is incompletely understood. Isoproterenol (ISO) was used to induce cardiomyocyte hypertrophy, and autocamtide-2-related inhibitory

Transient receptor potential vanilloid subfamily member 1 (TRPV1) is a nonselective cation channel, that is mainly distributed in sensory nerve endings and can release a variety of neurotransmitters after activation. Early studies showed that it mainly conducts pain sensation, but research has demonstrated that it also plays an important role in cardiovascular diseases. Notably, in atherosclerosis

Cav3.2 T-type calcium channels play an essential role in the transmission of peripheral nociception in the dorsal root ganglia (DRG) and alteration of Cav3.2 expression is associated with the development of peripheral painful diabetic neuropathy (PDN). Several studies have previously documented the role of glycosylation in the expression and functioning of Cav3.2 and suggested that altered glycosylation

Activation of protein kinase A by cyclic AMP results in a multi-fold upregulation of CaV1.2 currents in the heart, as originally reported in the 1970's and 1980's. Despite considerable interest and much investment, the molecular mechanisms responsible for this signature modulation remained stubbornly elusive for over 40 years. A key manifestation of this lack of understanding is that while this regulation

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are expressed throughout the mammalian central nervous system (CNS). These channels have been implicated in a wide range of diseases, including Major Depressive Disorder and multiple subtypes of epilepsy. The diversity of functions that HCN channels perform is in part attributable to differences in their subcellular localization. To

Transient receptor potential (TRP) channels form a family of polymodal cation channels gated by thermal, mechanical, or chemical stimuli, with many of them involved in the control of proliferation, apoptosis, or cell cycle. From an evolutionary point of view, TRP family is characterized by high conservation of duplicated genes originating from whole-genome duplication at the onset of vertebrates. The

(2020). T-type channels in neuropathic pain - Villain or victim? Channels: Vol. 14, No. 1, pp. 98-100.

Background and Purpose: Ion-channels are membrane proteins that can adopt several distinct structural conformations. Some of the conformations are open and allow the passage of ions through the membrane; others are closed and hinder ion flow. Patch-clamp recordings of single ion-channels show if a channel is open or closed, but does not immediately reveal the underlying mechanism, which typically includes

The Transient Receptor Potential Melastatin 8 (TRPM8) ion channel is an important sensor of environmental cold temperatures. Cold- and menthol-induced activation of this channel requires the presence of the membrane phospholipid phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]. This review discusses recent findings on the role of PI(4,5)P2 and G-proteins in the modulation of TRPM8 upon receptor activation

Neuropathic pain is clinically unsatisfactorily treated because of unclear mechanisms. The present study aims to explore the concrete mechanisms underlying the alleviation of resveratrol-activated silent information regulator 1 (Sirt1) to chronic constriction injury (CCI)-induced neuropathic pain. CCI surgery was conducted to the unilateral sciatic nerve of male Sprague-Dawley rats to induce neuropathic

The natural outcome of abdominal aortic aneurysm (AAA) is that of slow progression and ultimate rupture, then a life-threatening hemorrhage consequently. Ruptured AAA is a dramatic catastrophe and constitutes one of the leading causes of acute death in elderly men. However, the mechanism of AAA is still unclear. Transient receptor potential vanilloid (TRPV) family has protective effects in cardiovascular

Severe local acidosis causes tissue damage and pain, and is associated with many diseases, including cerebral and cardiac ischemia, cancer, infection, and inflammation. However, the molecular mechanisms of the cellular response to extracellular acidic environment are not fully understood. We recently identified a novel and evolutionarily conserved membrane protein, PAC (also known as PACC1 or TMEM206)

Assessing the expression of channels on the cell membrane is a necessary step in studying the functioning of ion channels in living cells. We explore, first, if endogenous VRAC can be assayed using flow cytometry and a commercially available antibody against an extracellular loop of the LRRC8A, also known as SWELL1, subunit of the VRAC channel. The second goal is to determine if an increase in the

In mammalian cells, one-third of all polypeptides is transported into or through the ER-membrane via the Sec61-channel. While the Sec61-complex facilitates the transport of all polypeptides with amino-terminal signal peptides (SP) or SP-equivalent transmembrane helices (TMH), the translocating chain-associated membrane protein (now termed TRAM1) was proposed to support transport of a subset of precursors

ABSTRACT ABSTRACT Objective: To explore the research status, hotspots, and trends in research on potassium channel. Methods: The Web of Science core collection database was used as the data source and the visual analysis software Citespace5.4 R3 was used to visualize the studies of potassium channel in the past 10 years. The national/institutional distribution, journal distribution, authors, and related

ABSTRACT Voltage gated sodium channels (Nav) play a crucial role in action potential initiation and propagation. Although the discovery of Nav channels dates back more than 65 years, and great advances in understanding their localization, biophysical properties, and links to disease have been made, there are still many questions to be answered regarding the cellular and molecular mechanisms involved

Vascular smooth muscle cells (VSMCs) of small peripheral arteries contribute to blood pressure control by adapting their contractile state. These adaptations depend on the VSMC cytosolic Ca2+ concentration, regulated by complex local elementary Ca2+ signaling pathways. Ca2+ sparks represent local, transient, rapid calcium release events from a cluster of ryanodine receptors (RyRs) in the sarcoplasmic

PI 3-kinase α (PI3Kα) is a lipid kinase that converts phosphatidylinositol-4,5-bisphosphate (PIP2) to phosphatidylinositol-3,4,5-triphosphate (PIP3). PI3Kα regulates a variety of cellular processes such as nutrient sensing, cell cycle, migration, and others. Heightened activity of PI3Kα in many types of cancer made it a prime oncology drug target, but also raises concerns of possible adverse effects

KCNE β-subunits play critical roles in modulating cardiac voltage-gated potassium channels. Among them, KCNE1 associates with KCNQ1 channel to confer a slow-activated IKs current, while KCNE2 functions as a dominant negative modulator to suppress the current amplitude of KCNQ1. Any anomaly in these channels will lead to serious myocardial diseases, such as the long QT syndrome (LQTS). Trafficking defects

We have previously reported that the microtubule-associated collapsin response mediator protein 2 (CRMP2) is necessary for the expression of chronic pain. CRMP2 achieves this control of nociceptive signaling by virtue of its ability to regulate voltage-gated calcium and sodium channels. To date, however, no drugs exist that target CRMP2. Recently, the small molecule edonerpic maleate (1 -{3-[2-(1-

The discovery of Acid-sensing ion channels (ASICs) provided us the theoretical basis to understand the pathological acidic environment. They belong to the degenerin/epithelial Na+ channel family and function once extracellular pH decreases to a certain level, and this characteristic make them spotlights in the regulation or response of pH change. As a regulatory system, keeping the intra- and extra-balance

See also: Tombola F, Ulbrich MH, Kohout SC, Isacoff EY. The opening of the two pores of the Hv1 voltage-gated proton channel is tuned by cooperativity. Nat Struct Mol Biol 2010; 17:44-50; PMID: 20023640; DOI: 10.1038/nsmb.1738.

The aim of the present study was to investigate in detail how the voltage sensor in the Shaker potassium channel moves during the gating process. After the publication of the open channel structure from the crystallized K(V)AP channel in 2003, an alternative so-called "paddle" model was put forward in contrast to the existing helical screw model. The voltage sensor S4 contains 4 arginine residues relevant

The K(V)7 (KCNQ) subfamily of voltage-gated K(+) channels consists of five members (K(V)7.1-K(V)7.5) giving rise to non-inactivating, and slowly activating/deactivating currents mainly expressed in cardiac (K(V)7.1) and neuronal (K(V)7.2-K(V)7.5) tissue. In the present study, using the cut-open oocyte voltage clamp, we studied the relation of the ionic currents from homomeric neuronal K(V)7 channels

Drug induced Long QT syndrome results primarily from block of the cardiac potassium channel HERG (human-ether-a-go-go related gene). In some cases prolongation of the QT interval can result in the lethal arrhythmia torsade de pointes, an arrhythmia characterized by a rapid heart rate and severely compromised cardiac output. Many patients requiring medication present with abnormal serum electrolyte

Cellular defects in ankyrin-based ion channels and transporter targeting pathways have previously been linked with abnormal vertebrate physiology and human disease. In a recent study, our group linked dysfunction in cardiac ankyrin-B function with human sinus node disease. Ankyrin-B deficient mice displayed bradycardia and heart rate variability similar to individuals harboring an ANK2 variant. Isolated

Tetrodotoxin (TTX) is a potent toxin that specifically binds to voltage gated sodium channels. TTX binding physically blocks the flow of sodium ions through the channel, thereby preventing action potential (AP) generation and propagation. TTX has different binding affinities for different sodium channel isoforms. These differences are imparted by amino acid substitutions. Such substitutions confer

Evidence supports a role for the tetrodotoxin-sensitive Na(V)1.7 and the tetrodotoxin-resistant Na(V)1.8 in the pathogenesis of pain. Ranolazine, an anti-ischemic drug, has been shown to block cardiac (Na(V)1.5) late sodium current (I(Na)). In this study, whole-cell patch-clamp techniques were used to determine the effects of ranolazine on human Na(V)1.7 (hNa(V)1.7 + beta(1) subunits) and rat Na(V)1

Ion-coupled secondary transport is utilized by a broad range of integral membrane proteins to catalyze the energetically unfavorable movement of solute molecules across a lipid bilayer. Members of the solute carrier 6 (SLC6) family, present in both prokaryotes and eukaryotes, are sodium-coupled symporters that play crucial roles in processes as diverse as nutrient uptake and neurotransmitter clearance

The nicotinic acetylcholine receptor (nAChR) is a ligand-gated ion channel protein that mediates fast excitatory synaptic transmission in the peripheral and central nervous systems. Changes in the structure and function of the AChR can lead to serious impairment of physiological processes. In this study, we combined site-directed mutagenesis, radioligand binding assays, electrophysiological recordings

Anion exchanger proteins facilitate the exchange of bicarbonate for chloride across the plasma membrane. When bicarbonate combines with a proton it undergoes conversion into CO₂, either spontaneously, or catalyzed by carbonic anhydrase enzymes. The CO₂/HCO₃⁻ equilibrium is the body's central pH buffering system. Rapid bicarbonate transport across the plasma membrane is essential to maintain cellular

KAAT1 and CAATCH1 are amino acid transporters cloned from the intestine of the lepidoptera Manduca sexta. They are members of the SLC6/NSS family, which groups membrane proteins that use Na(+), K(+), and Cl⁻ gradients for the coupled transport of amines and amino acids. The report of the atomic-resolution x-ray crystal structure of the eubacterium Aquifex aeolicus leucine transporter (AaLeuT) has contributed

Sodium proton exchangers (NHEs) constitute a large family of polytopic membrane protein transporters found in organisms across all domains of life. They are responsible for the exchange of protons for sodium ions. In archaea, bacteria, yeast and plants they provide increased salt tolerance by removing sodium in exchanger for extracellular protons. In humans they have a host of physiological functions

Transporters represent attractive targets for drug discovery and are implicated in the pathophysiology of disorders across several therapeutic areas including asthma, cardiovascular disease, diabetes and neuroscience. However, the intrinsic mechanistic properties of transporters present significant challenges to the development of high-throughput screening methodologies. This review provides an update

As the number of high-resolution structures of membrane proteins continues to rise, so has the necessity for techniques to link this structural information to protein function. In the case of transporters, function is achieved via coupling of conformational changes to substrate binding and release. Static structural data alone cannot convey information on these protein movements, but it can provide

The Na(+)-Ca(2+) exchanger (NCX) links transmembrane movements of Ca(2+) ions to the reciprocal movement of Na(+) ions. It normally functions primarily as a Ca(2+) efflux mechanism in excitable tissues such as the heart, but it can also mediate Ca(2+) influx under certain conditions. Na(+) and Ca(2+) ions exert complex regulatory effects on NCX activity. Ca(2+) binds to two regulatory sites in the

Na(+)-coupled phosphate cotransporters of the SLC34 gene family catalyze the movement of inorganic phosphate (P(i)) across epithelia by using the free energy of the downhill electrochemical Na(+) gradient across the luminal membrane. Electrogenic (NaPi-IIa/b) and electroneutral (NaPi-IIc) isoforms prefer divalent P(i) and show strict Na(+):P(i) stoichiometries of 3:1 and 2:1, respectively. For electrogenic