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18 pages, 3795 KiB

Open AccessArticle

Regulation and Function of TMEM16F in Renal Podocytes

by Laura K. Schenk, Jiraporn Ousingsawat, Boris V. Skryabin, Rainer Schreiber, Hermann Pavenstädt and Karl Kunzelmann

Int. J. Mol. Sci. 2018, 19(6), 1798; https://doi.org/10.3390/ijms19061798 - 18 Jun 2018

Cited by 5 | Viewed by 5073

Abstract

The Ca²⁺-activated phospholipid scramblase and ion channel TMEM16F is expressed in podocytes of renal glomeruli. Podocytes are specialized cells that form interdigitating foot processes as an essential component of the glomerular filter. These cells, which participate in generation of the primary [...] Read more.

The Ca²⁺-activated phospholipid scramblase and ion channel TMEM16F is expressed in podocytes of renal glomeruli. Podocytes are specialized cells that form interdigitating foot processes as an essential component of the glomerular filter. These cells, which participate in generation of the primary urine, are often affected during primary glomerular diseases, such as glomerulonephritis and secondary hypertensive or diabetic nephropathy, which always leads to proteinuria. Because the function of podocytes is known to be controlled by intracellular Ca²⁺ signaling, it is important to know about the role of Ca²⁺-activated TMEM16F in these cells. To that end, we generated an inducible TMEM16F knockdown in the podocyte cell line AB8, and produced a conditional mouse model with knockout of TMEM16F in podocytes and renal epithelial cells of the nephron. We found that knockdown of TMEM16F did not produce proteinuria or any obvious phenotypic changes. Knockdown of TMEM16F affected cell death of tubular epithelial cells but not of glomerular podocytes when analyzed in TUNEL assays. Surprisingly, and in contrast to other cell types, TMEM16F did not control intracellular Ca²⁺ signaling and was not responsible for Ca²⁺-activated whole cell currents in podocytes. TMEM16F levels in podocytes were enhanced after inhibition of the endolysosomal pathway and after treatment with angiotensin II. Renal knockout of TMEM16F did not compromise renal morphology and serum electrolytes. Taken together, in contrast to other cell types, such as platelets, bone cells, and immune cells, TMEM16F shows little effect on basal properties of podocytes and does not appear to be essential for renal function. Full article

(This article belongs to the Special Issue Ion Transporters and Channels in Physiology and Pathophysiology)

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14 pages, 1293 KiB

Open AccessArticle

Regulation of Bicarbonate Secretion in Marine Fish Intestine by the Calcium-Sensing Receptor

by Sílvia F. Gregório and Juan Fuentes

Int. J. Mol. Sci. 2018, 19(4), 1072; https://doi.org/10.3390/ijms19041072 - 4 Apr 2018

Cited by 14 | Viewed by 4117

Abstract

In marine fish, high epithelial intestinal HCO₃⁻ secretion generates luminal carbonate precipitates of divalent cations that play a key role in water and ion homeostasis. The present study was designed to expose the putative role for calcium and the calcium-sensing receptor [...] Read more.

In marine fish, high epithelial intestinal HCO₃⁻ secretion generates luminal carbonate precipitates of divalent cations that play a key role in water and ion homeostasis. The present study was designed to expose the putative role for calcium and the calcium-sensing receptor (CaSR) in the regulation of HCO₃⁻ secretion in the intestine of the sea bream (Sparus aurata L.). Effects on the expression of the CaSR in the intestine were evaluated by qPCR and an increase was observed in the anterior intestine in fed fish compared with unfed fish and with different regions of intestine. CaSR expression reflected intestinal fluid calcium concentration. In addition, anterior intestine tissue was mounted in Ussing chambers to test the putative regulation of HCO₃⁻ secretion in vitro using the anterior intestine. HCO₃⁻ secretion was sensitive to varying calcium levels in luminal saline and to calcimimetic compounds known to activate/block the CaSR i.e., R 568 and NPS-2143. Subsequent experiments were performed in intestinal sacs to measure water absorption and the sensitivity of water absorption to varying luminal levels of calcium and calcimimetics were exposed as well. It appears, that CaSR mediates HCO₃⁻ secretion and water absorption in marine fish as shown by responsiveness to calcium levels and calcimimetic compounds. Full article

(This article belongs to the Special Issue Ion Transporters and Channels in Physiology and Pathophysiology)

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17 pages, 1810 KiB

Open AccessArticle

A Finite Element Solution of Lateral Periodic Poisson–Boltzmann Model for Membrane Channel Proteins

by Nan Ji, Tiantian Liu, Jingjie Xu, Longzhu Q. Shen and Benzhuo Lu

Int. J. Mol. Sci. 2018, 19(3), 695; https://doi.org/10.3390/ijms19030695 - 28 Feb 2018

Cited by 10 | Viewed by 4061

Abstract

Membrane channel proteins control the diffusion of ions across biological membranes. They are closely related to the processes of various organizational mechanisms, such as: cardiac impulse, muscle contraction and hormone secretion. Introducing a membrane region into implicit solvation models extends the ability of [...] Read more.

Membrane channel proteins control the diffusion of ions across biological membranes. They are closely related to the processes of various organizational mechanisms, such as: cardiac impulse, muscle contraction and hormone secretion. Introducing a membrane region into implicit solvation models extends the ability of the Poisson–Boltzmann (PB) equation to handle membrane proteins. The use of lateral periodic boundary conditions can properly simulate the discrete distribution of membrane proteins on the membrane plane and avoid boundary effects, which are caused by the finite box size in the traditional PB calculations. In this work, we: (1) develop a first finite element solver (FEPB) to solve the PB equation with a two-dimensional periodicity for membrane channel proteins, with different numerical treatments of the singular charges distributions in the channel protein; (2) add the membrane as a dielectric slab in the PB model, and use an improved mesh construction method to automatically identify the membrane channel/pore region even with a tilt angle relative to the z-axis; and (3) add a non-polar solvation energy term to complete the estimation of the total solvation energy of a membrane protein. A mesh resolution of about 0.25 Å (cubic grid space)/0.36 Å (tetrahedron edge length) is found to be most accurate in linear finite element calculation of the PB solvation energy. Computational studies are performed on a few exemplary molecules. The results indicate that all factors, the membrane thickness, the length of periodic box, membrane dielectric constant, pore region dielectric constant, and ionic strength, have individually considerable influence on the solvation energy of a channel protein. This demonstrates the necessity to treat all of those effects in the PB model for membrane protein simulations. Full article

(This article belongs to the Special Issue Ion Transporters and Channels in Physiology and Pathophysiology)

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13 pages, 1256 KiB

Open AccessArticle

Seihai-to (TJ-90)-Induced Activation of Airway Ciliary Beatings of Mice: Ca²⁺ Modulation of cAMP-Stimulated Ciliary Beatings via PDE1

by Haruka Kogiso, Yukiko Ikeuchi, Masako Sumiya, Shigekuni Hosogi, Saori Tanaka, Chikao Shimamoto, Toshio Inui, Yoshinori Marunaka and Takashi Nakahari

Int. J. Mol. Sci. 2018, 19(3), 658; https://doi.org/10.3390/ijms19030658 - 26 Feb 2018

Cited by 15 | Viewed by 3649

Abstract

Sei-hai-to (TJ-90, Qing Fei Tang), a Chinese traditional medicine, increases ciliary beat frequency (CBF) and ciliary bend angle (CBA) mediated via cAMP (3′,5′-cyclic adenosine monophosphate) accumulation modulated by Ca²⁺-activated phosphodiesterase 1 (PDE1A). A high concentration of TJ-90 (≥40 μg/mL) induced two [...] Read more.

Sei-hai-to (TJ-90, Qing Fei Tang), a Chinese traditional medicine, increases ciliary beat frequency (CBF) and ciliary bend angle (CBA) mediated via cAMP (3′,5′-cyclic adenosine monophosphate) accumulation modulated by Ca²⁺-activated phosphodiesterase 1 (PDE1A). A high concentration of TJ-90 (≥40 μg/mL) induced two types of CBF increases, a transient increase (an initial increase, followed by a decrease) and a sustained increase without any decline, while it only sustained the CBA increase. Upon inhibiting increases in intracellular Ca²⁺ concentration ([Ca²⁺]_i) by 10 μM BAPTA-AM (Ca²⁺-chelator, 1,2-Bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetrakis(acetoxymethyl ester) or Ca²⁺/calmodulin-dependent PDE1 by 8MmIBMX (a selective PDE1 inhibitor), TJ-90 (400 μg/mL) induced only the sustained CBF increase without any transient CBF increase. The two types of the CBF increase (the transient increase and the sustained increase) induced by TJ-90 (≥40 μg/mL) were mimicked by the stimulation with both procaterol (100 pM) and ionomycin (500 nM). Thus, TJ-90 stimulates small increases in the intracellular cAMP concentration ([cAMP]_i) and [Ca²⁺]_i in airway ciliary cells of mice. These small increases in [cAMP]_i and [Ca²⁺]_i cause inducing a transient CBF increase or a sustained CBF increase in an airway ciliary cells, depending on the dominant signal, Ca²⁺-signal, or cAMP-signal. Full article

(This article belongs to the Special Issue Ion Transporters and Channels in Physiology and Pathophysiology)

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20 pages, 2722 KiB

Open AccessArticle

Sinus Bradycardia in Carriers of the SCN5A-1795insD Mutation: Unraveling the Mechanism through Computer Simulations

by Ronald Wilders

Int. J. Mol. Sci. 2018, 19(2), 634; https://doi.org/10.3390/ijms19020634 - 23 Feb 2018

Cited by 11 | Viewed by 5193

Abstract

The SCN5A gene encodes the pore-forming α-subunit of the ion channel that carries the cardiac fast sodium current (I_Na). The 1795insD mutation in SCN5A causes sinus bradycardia, with a mean heart rate of 70 beats/min in mutation carriers vs. 77 [...] Read more.

The SCN5A gene encodes the pore-forming α-subunit of the ion channel that carries the cardiac fast sodium current (I_Na). The 1795insD mutation in SCN5A causes sinus bradycardia, with a mean heart rate of 70 beats/min in mutation carriers vs. 77 beats/min in non-carriers from the same family (lowest heart rate 41 vs. 47 beats/min). To unravel the underlying mechanism, we incorporated the mutation-induced changes in I_Na into a recently developed comprehensive computational model of a single human sinoatrial node cell (Fabbri–Severi model). The 1795insD mutation reduced the beating rate of the model cell from 74 to 69 beats/min (from 49 to 43 beats/min in the simulated presence of 20 nmol/L acetylcholine). The mutation-induced persistent I_Na per se resulted in a substantial increase in beating rate. This gain-of-function effect was almost completely counteracted by the loss-of-function effect of the reduction in I_Na conductance. The further loss-of-function effect of the shifts in steady-state activation and inactivation resulted in an overall loss-of-function effect of the 1795insD mutation. We conclude that the experimentally identified mutation-induced changes in I_Na can explain the clinically observed sinus bradycardia. Furthermore, we conclude that the Fabbri–Severi model may prove a useful tool in understanding cardiac pacemaker activity in humans. Full article

(This article belongs to the Special Issue Ion Transporters and Channels in Physiology and Pathophysiology)

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16 pages, 5175 KiB

Open AccessArticle

Mitochondrial BK Channel Openers CGS7181 and CGS7184 Exhibit Cytotoxic Properties

by Bartłomiej Augustynek, Piotr Koprowski, Daria Rotko, Wolfram S. Kunz, Adam Szewczyk and Bogusz Kulawiak

Int. J. Mol. Sci. 2018, 19(2), 353; https://doi.org/10.3390/ijms19020353 - 25 Jan 2018

Cited by 18 | Viewed by 6808

Abstract

Potassium channel openers (KCOs) have been shown to play a role in cytoprotection through the activation of mitochondrial potassium channels. Recently, in several reports, a number of data has been described as off-target actions for KCOs. In the present study, we investigated the [...] Read more.

Potassium channel openers (KCOs) have been shown to play a role in cytoprotection through the activation of mitochondrial potassium channels. Recently, in several reports, a number of data has been described as off-target actions for KCOs. In the present study, we investigated the effects of BK_Ca channel openers CGS7181, CGS7184, NS1619, and NS004 in neuronal cells. For the purpose of this research, we used a rat brain, the mouse hippocampal HT22 cells, and the human astrocytoma U-87 MG cell line. We showed that CGS7184 activated the mitochondrial BK_Ca (mitoBK_Ca) channel in single-channel recordings performed on astrocytoma mitoplasts. Moreover, when applied to the rat brain homogenate or isolated rat brain mitochondria, CGS7184 increased the oxygen consumption rate, and can thus be considered a potentially cytoprotective agent. However, experiments on intact neuronal HT22 cells revealed that both CGS7181 and CGS7184 induced HT22 cell death in a concentration- and time-dependent manner. By contrast, we did not observe cell death when NS1619 or NS004 was applied. CGS7184 toxicity was not abolished by BK_Ca channel inhibitors, suggesting that the observed effects were independent of a BK_Ca-type channel activity. CGS7184 treatment resulted in an increase of cytoplasmic Ca²⁺ concentration that likely involved efflux from internal calcium stores and the activation of calpains (calcium-dependent proteases). The cytotoxic effect of the channel opener was partially reversed by a calpain inhibitor. Our data show that KCOs under study not only activate mitoBK_Ca channels from brain tissue, but also induce cell death when used in cellular models. Full article

(This article belongs to the Special Issue Ion Transporters and Channels in Physiology and Pathophysiology)

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22 pages, 7457 KiB

Open AccessArticle

Functional Testing of SLC26A4 Variants—Clinical and Molecular Analysis of a Cohort with Enlarged Vestibular Aqueduct from Austria

by Sebastian Roesch, Emanuele Bernardinelli, Charity Nofziger, Miklós Tóth, Wolfgang Patsch, Gerd Rasp, Markus Paulmichl and Silvia Dossena

Int. J. Mol. Sci. 2018, 19(1), 209; https://doi.org/10.3390/ijms19010209 - 10 Jan 2018

Cited by 16 | Viewed by 4897

Abstract

The prevalence and spectrum of sequence alterations in the SLC26A4 gene, which codes for the anion exchanger pendrin, are population-specific and account for at least 50% of cases of non-syndromic hearing loss associated with an enlarged vestibular aqueduct. A cohort of nineteen patients [...] Read more.

The prevalence and spectrum of sequence alterations in the SLC26A4 gene, which codes for the anion exchanger pendrin, are population-specific and account for at least 50% of cases of non-syndromic hearing loss associated with an enlarged vestibular aqueduct. A cohort of nineteen patients from Austria with hearing loss and a radiological alteration of the vestibular aqueduct underwent Sanger sequencing of SLC26A4 and GJB2, coding for connexin 26. The pathogenicity of sequence alterations detected was assessed by determining ion transport and molecular features of the corresponding SLC26A4 protein variants. In this group, four uncharacterized sequence alterations within the SLC26A4 coding region were found. Three of these lead to protein variants with abnormal functional and molecular features, while one should be considered with no pathogenic potential. Pathogenic SLC26A4 sequence alterations were only found in 12% of patients. SLC26A4 sequence alterations commonly found in other Caucasian populations were not detected. This survey represents the first study on the prevalence and spectrum of SLC26A4 sequence alterations in an Austrian cohort and further suggests that genetic testing should always be integrated with functional characterization and determination of the molecular features of protein variants in order to unequivocally identify or exclude a causal link between genotype and phenotype. Full article

(This article belongs to the Special Issue Ion Transporters and Channels in Physiology and Pathophysiology)

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Review

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17 pages, 514 KiB

Open AccessReview

Zebrafish as a Model System for Investigating the Compensatory Regulation of Ionic Balance during Metabolic Acidosis

by Lletta Lewis and Raymond W. M. Kwong

Int. J. Mol. Sci. 2018, 19(4), 1087; https://doi.org/10.3390/ijms19041087 - 5 Apr 2018

Cited by 18 | Viewed by 8716

Abstract

Zebrafish (Danio rerio) have become an important model for integrative physiological research. Zebrafish inhabit a hypo-osmotic environment; to maintain ionic and acid-base homeostasis, they must actively take up ions and secrete acid to the water. The gills in the adult and [...] Read more.

Zebrafish (Danio rerio) have become an important model for integrative physiological research. Zebrafish inhabit a hypo-osmotic environment; to maintain ionic and acid-base homeostasis, they must actively take up ions and secrete acid to the water. The gills in the adult and the skin at larval stage are the primary sites of ionic regulation in zebrafish. The uptake of ions in zebrafish is mediated by specific ion transporting cells termed ionocytes. Similarly, in mammals, ion reabsorption and acid excretion occur in specific cell types in the terminal region of the renal tubules (distal convoluted tubule and collecting duct). Previous studies have suggested that functional regulation of several ion transporters/channels in the zebrafish ionocytes resembles that in the mammalian renal cells. Additionally, several mechanisms involved in regulating the epithelial ion transport during metabolic acidosis are found to be similar between zebrafish and mammals. In this article, we systemically review the similarities and differences in ionic regulation between zebrafish and mammals during metabolic acidosis. We summarize the available information on the regulation of epithelial ion transporters during acidosis, with a focus on epithelial Na⁺, Cl⁻ and Ca²⁺ transporters in zebrafish ionocytes and mammalian renal cells. We also discuss the neuroendocrine responses to acid exposure, and their potential role in ionic compensation. Finally, we identify several knowledge gaps that would benefit from further study. Full article

(This article belongs to the Special Issue Ion Transporters and Channels in Physiology and Pathophysiology)

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26 pages, 1282 KiB

Open AccessReview

ATP Release Channels

by Akiyuki Taruno

Int. J. Mol. Sci. 2018, 19(3), 808; https://doi.org/10.3390/ijms19030808 - 11 Mar 2018

Cited by 151 | Viewed by 10201

Abstract

Adenosine triphosphate (ATP) has been well established as an important extracellular ligand of autocrine signaling, intercellular communication, and neurotransmission with numerous physiological and pathophysiological roles. In addition to the classical exocytosis, non-vesicular mechanisms of cellular ATP release have been demonstrated in many cell [...] Read more.

Adenosine triphosphate (ATP) has been well established as an important extracellular ligand of autocrine signaling, intercellular communication, and neurotransmission with numerous physiological and pathophysiological roles. In addition to the classical exocytosis, non-vesicular mechanisms of cellular ATP release have been demonstrated in many cell types. Although large and negatively charged ATP molecules cannot diffuse across the lipid bilayer of the plasma membrane, conductive ATP release from the cytosol into the extracellular space is possible through ATP-permeable channels. Such channels must possess two minimum qualifications for ATP permeation: anion permeability and a large ion-conducting pore. Currently, five groups of channels are acknowledged as ATP-release channels: connexin hemichannels, pannexin 1, calcium homeostasis modulator 1 (CALHM1), volume-regulated anion channels (VRACs, also known as volume-sensitive outwardly rectifying (VSOR) anion channels), and maxi-anion channels (MACs). Recently, major breakthroughs have been made in the field by molecular identification of CALHM1 as the action potential-dependent ATP-release channel in taste bud cells, LRRC8s as components of VRACs, and SLCO2A1 as a core subunit of MACs. Here, the function and physiological roles of these five groups of ATP-release channels are summarized, along with a discussion on the future implications of understanding these channels. Full article

(This article belongs to the Special Issue Ion Transporters and Channels in Physiology and Pathophysiology)

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20 pages, 1415 KiB

Open AccessReview

Diabetes Mellitus and Ischemic Heart Disease: The Role of Ion Channels

by Paolo Severino, Andrea D’Amato, Lucrezia Netti, Mariateresa Pucci, Marialaura De Marchis, Raffaele Palmirotta, Maurizio Volterrani, Massimo Mancone and Francesco Fedele

Int. J. Mol. Sci. 2018, 19(3), 802; https://doi.org/10.3390/ijms19030802 - 10 Mar 2018

Cited by 50 | Viewed by 8670

Abstract

Diabetes mellitus is one the strongest risk factors for cardiovascular disease and, in particular, for ischemic heart disease (IHD). The pathophysiology of myocardial ischemia in diabetic patients is complex and not fully understood: some diabetic patients have mainly coronary stenosis obstructing blood flow [...] Read more.

Diabetes mellitus is one the strongest risk factors for cardiovascular disease and, in particular, for ischemic heart disease (IHD). The pathophysiology of myocardial ischemia in diabetic patients is complex and not fully understood: some diabetic patients have mainly coronary stenosis obstructing blood flow to the myocardium; others present with coronary microvascular disease with an absence of plaques in the epicardial vessels. Ion channels acting in the cross-talk between the myocardial energy state and coronary blood flow may play a role in the pathophysiology of IHD in diabetic patients. In particular, some genetic variants for ATP-dependent potassium channels seem to be involved in the determinism of IHD. Full article

(This article belongs to the Special Issue Ion Transporters and Channels in Physiology and Pathophysiology)

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15 pages, 806 KiB

Open AccessReview

Regulation of Ion Transport in the Intestine by Free Fatty Acid Receptor 2 and 3: Possible Involvement of the Diffuse Chemosensory System

by Atsukazu Kuwahara, Yuko Kuwahara, Toshio Inui and Yoshinori Marunaka

Int. J. Mol. Sci. 2018, 19(3), 735; https://doi.org/10.3390/ijms19030735 - 5 Mar 2018

Cited by 7 | Viewed by 4719

Abstract

The diffuse chemosensory system (DCS) is well developed in the apparatuses of endodermal origin like gastrointestinal (GI) tract. The primary function of the GI tract is the extraction of nutrients from the diet. Therefore, the GI tract must possess an efficient surveillance system [...] Read more.

The diffuse chemosensory system (DCS) is well developed in the apparatuses of endodermal origin like gastrointestinal (GI) tract. The primary function of the GI tract is the extraction of nutrients from the diet. Therefore, the GI tract must possess an efficient surveillance system that continuously monitors the luminal contents for beneficial or harmful compounds. Recent studies have shown that specialized cells in the intestinal lining can sense changes in the luminal content. The chemosensory cells in the GI tract belong to the DCS which consists of enteroendocrine and related cells. These cells initiate various important local and remote reflexes. Although neural and hormonal involvements in ion transport in the GI tract are well documented, involvement of the DCS in the regulation of intestinal ion transport is much less understood. Since activation of luminal chemosensory receptors is a primary signal that elicits changes in intestinal ion transport and motility and failure of the system causes dysfunctions in host homeostasis, as well as functional GI disorders, study of the regulation of GI function by the DCS has become increasingly important. This review discusses the role of the DCS in epithelial ion transport, with particular emphasis on the involvement of free fatty acid receptor 2 (FFA2) and free fatty acid receptor 3 (FFA3). Full article

(This article belongs to the Special Issue Ion Transporters and Channels in Physiology and Pathophysiology)

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12 pages, 891 KiB

Open AccessReview

Expression of LRRC8/VRAC Currents in Xenopus Oocytes: Advantages and Caveats

by Héctor Gaitán-Peñas, Michael Pusch and Raúl Estévez

Int. J. Mol. Sci. 2018, 19(3), 719; https://doi.org/10.3390/ijms19030719 - 2 Mar 2018

Cited by 11 | Viewed by 4553

Abstract

Volume-regulated anion channels (VRACs) play a role in controlling cell volume by opening upon cell swelling. Apart from controlling cell volume, their function is important in many other physiological processes, such as transport of metabolites or drugs, and extracellular signal transduction. VRACs are [...] Read more.

Volume-regulated anion channels (VRACs) play a role in controlling cell volume by opening upon cell swelling. Apart from controlling cell volume, their function is important in many other physiological processes, such as transport of metabolites or drugs, and extracellular signal transduction. VRACs are formed by heteromers of the pannexin homologous protein LRRC8A (also named Swell1) with other LRRC8 members (B, C, D, and E). LRRC8 proteins are difficult to study, since they are expressed in all cells of our body, and the channel stoichiometry can be changed by overexpression, resulting in non-functional heteromers. Two different strategies have been developed to overcome this issue: complementation by transient transfection of LRRC8 genome-edited cell lines, and reconstitution in lipid bilayers. Alternatively, we have used Xenopus oocytes as a simple system to study LRRC8 proteins. Here, we have reviewed all previous experiments that have been performed with VRAC and LRRC8 proteins in Xenopus oocytes. We also discuss future strategies that may be used to perform structure-function analysis of the VRAC in oocytes and other systems, in order to understand its role in controlling multiple physiological functions. Full article

(This article belongs to the Special Issue Ion Transporters and Channels in Physiology and Pathophysiology)

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30 pages, 10070 KiB

Open AccessReview

Ion Channel Disorders and Sudden Cardiac Death

by Anna Garcia-Elias and Begoña Benito

Int. J. Mol. Sci. 2018, 19(3), 692; https://doi.org/10.3390/ijms19030692 - 28 Feb 2018

Cited by 65 | Viewed by 11079

Abstract

Long QT syndrome, short QT syndrome, Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia are inherited primary electrical disorders that predispose to sudden cardiac death in the absence of structural heart disease. Also known as cardiac channelopathies, primary electrical disorders respond to mutations in [...] Read more.

Long QT syndrome, short QT syndrome, Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia are inherited primary electrical disorders that predispose to sudden cardiac death in the absence of structural heart disease. Also known as cardiac channelopathies, primary electrical disorders respond to mutations in genes encoding cardiac ion channels and/or their regulatory proteins, which result in modifications in the cardiac action potential or in the intracellular calcium handling that lead to electrical instability and life-threatening ventricular arrhythmias. These disorders may have low penetrance and expressivity, making clinical diagnosis often challenging. However, because sudden cardiac death might be the first presenting symptom of the disease, early diagnosis becomes essential. Genetic testing might be helpful in this regard, providing a definite diagnosis in some patients. Yet important limitations still exist, with a significant proportion of patients remaining with no causative mutation identifiable after genetic testing. This review aims to provide the latest knowledge on the genetic basis of cardiac channelopathies and discuss the role of the affected proteins in the pathophysiology of each one of these diseases. Full article

(This article belongs to the Special Issue Ion Transporters and Channels in Physiology and Pathophysiology)

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20 pages, 1463 KiB

Open AccessReview

Endothelium-Dependent Hyperpolarization (EDH) in Hypertension: The Role of Endothelial Ion Channels

by Kenichi Goto, Toshio Ohtsubo and Takanari Kitazono

Int. J. Mol. Sci. 2018, 19(1), 315; https://doi.org/10.3390/ijms19010315 - 21 Jan 2018

Cited by 63 | Viewed by 15024

Abstract

Upon stimulation with agonists and shear stress, the vascular endothelium of different vessels selectively releases several vasodilator factors such as nitric oxide and prostacyclin. In addition, vascular endothelial cells of many vessels regulate the contractility of the vascular smooth muscle cells through the [...] Read more.

Upon stimulation with agonists and shear stress, the vascular endothelium of different vessels selectively releases several vasodilator factors such as nitric oxide and prostacyclin. In addition, vascular endothelial cells of many vessels regulate the contractility of the vascular smooth muscle cells through the generation of endothelium-dependent hyperpolarization (EDH). There is a general consensus that the opening of small- and intermediate-conductance Ca²⁺-activated K⁺ channels (SK_Ca and IK_Ca) is the initial mechanistic step for the generation of EDH. In animal models and humans, EDH and EDH-mediated relaxations are impaired during hypertension, and anti-hypertensive treatments restore such impairments. However, the underlying mechanisms of reduced EDH and its improvement by lowering blood pressure are poorly understood. Emerging evidence suggests that alterations of endothelial ion channels such as SK_Ca channels, inward rectifier K⁺ channels, Ca²⁺-activated Cl⁻ channels, and transient receptor potential vanilloid type 4 channels contribute to the impaired EDH during hypertension. In this review, we attempt to summarize the accumulating evidence regarding the pathophysiological role of endothelial ion channels, focusing on their relationship with EDH during hypertension. Full article

(This article belongs to the Special Issue Ion Transporters and Channels in Physiology and Pathophysiology)

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570 KiB

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Emerging Roles of TWIK-1 Heterodimerization in the Brain

by Chang-Hoon Cho, Eun Mi Hwang and Jae-Yong Park

Int. J. Mol. Sci. 2018, 19(1), 51; https://doi.org/10.3390/ijms19010051 - 24 Dec 2017

Cited by 6 | Viewed by 4044

Abstract

Two-pore domain K⁺ (K2P) channels play essential roles in regulating resting membrane potential and cellular excitability. Although TWIK-1 (TWIK—tandem of pore domains in a weak inward rectifying K⁺ channel) was the first identified member of the K2P channel family, it is [...] Read more.

Two-pore domain K⁺ (K2P) channels play essential roles in regulating resting membrane potential and cellular excitability. Although TWIK-1 (TWIK—tandem of pore domains in a weak inward rectifying K⁺ channel) was the first identified member of the K2P channel family, it is only in recent years that the physiological roles of TWIK-1 have been studied in depth. A series of reports suggest that TWIK-1 may underlie diverse functions, such as intrinsic excitability of neurons, astrocytic passive conductance, and astrocytic glutamate release, as a homodimer or heterodimer with other K2P isotypes. Here, we summarize expression patterns and newly identified functions of TWIK-1 in the brain. Full article

(This article belongs to the Special Issue Ion Transporters and Channels in Physiology and Pathophysiology)

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