Ion Channel Dysfunction Research Articles

Electrophysiological Remodeling: Cardiac T-Tubules and ß-Adrenoceptors.

Beta-adrenoceptors (βAR) are often viewed as archetypal G-protein coupled receptors. Over the past fifteen years, investigations in cardiovascular biology have provided remarkable insights into this receptor family. These studies have shifted pharmacological dogma, from one which centralized the receptor to a new focus on structural micro-domains such as caveolae and t-tubules. Important studies have examined, separately, the structural compartmentation of ion channels and βAR. Despite links being assumed, relatively few studies have specifically examined the direct link between structural remodeling and electrical remodeling with a focus on βAR. In this review, we will examine the nature of receptor and ion channel dysfunction on a substrate of cardiomyocyte microdomain remodeling, as well as the likely ramifications for cardiac electrophysiology. We will then discuss the advances in methodologies in this area with a specific focus on super-resolution microscopy, fluorescent imaging, and new approaches involving microdomain specific, polymer-based agonists. The advent of powerful computational modelling approaches has allowed the science to shift from purely empirical work, and may allow future investigations based on prediction. Issues such as the cross-reactivity of receptors and cellular heterogeneity will also be discussed. Finally, we will speculate as to the potential developments within this field over the next ten years.

ICDI-W2vCom: Identifying the Ion Channel-Drug Interaction in Cellular Networking Based on word2vec and node2vec.

Ion channels are the second largest drug target family. Ion channel dysfunction may lead to a number of diseases such as Alzheimer’s disease, epilepsy, cephalagra, and type II diabetes. In the research work for predicting ion channel–drug, computational approaches are effective and efficient compared with the costly, labor-intensive, and time-consuming experimental methods. Most of the existing methods can only be used to deal with the ion channels of knowing 3D structures; however, the 3D structures of most ion channels are still unknown. Many predictors based on protein sequence were developed to address the challenge, while most of their results need to be improved, or predicting web servers are missing. In this paper, a sequence-based classifier, called “iCDI-W2vCom,” was developed to identify the interactions between ion channels and drugs. In the predictor, the drug compound was formulated by SMILES-word2vec, FP2-word2vec, SMILES-node2vec, and ECFPs via a 1184D vector, ion channel was represented by the word2vec via a 64D vector, and the prediction engine was operated by the LightGBM classifier. The accuracy and AUC achieved by iCDI-W2vCom via the fivefold cross validation were 91.95% and 0.9703, which outperformed other existing predictors in this area. A user-friendly web server for iCDI-W2vCom was established at http://www.jci-bioinfo.cn/icdiw2v. The proposed method may also be a potential method for predicting target–drug interaction.

Intracellular potassium ion fluorescent nanoprobes for functional analysis of hERG channel via bioimaging

Dysfunction of potassium ion (K+) channels are closely related to various diseases, while the current tools for studying K+ channels are indirect methods that cannot measure the flux of K+ in live cells. Herein, we prepared K+ fluorescent nanoprobes (KFK-Cat NPs) with appropriate dissociation constant (Kd) value (127 mM K+) and excellent stability, especially photostability, for intracellular K+ sensing and imaging. An easy-operating and biocompatible method for functional measurement of human ether-a-go-go-related gene (hERG) channel activity was constructed via directly monitoring the fluctuation of K+ in KFK-Cat NPs stained hERG-HEK293 cells. Further, this method was efficient for screening of hERG channel inhibitors, the results were in accordance with the traditional patch-clamp technique and the commercially available thallium ion (Tl+) fluorescent probes assay kits. The KFK-Cat NPs were also capable of K+ imaging after endocytosed by hERG-overexpressing colon cancer cells. This work, for the first time, broadens the application of K+ fluorescent probes for functional analysis of K+ channels activity under the help of confocal laser scanning microscope (CLSM). This method shows significant potentials for drug screening and provides efficient tool for deep investigation of K+ channel-related diseases, including tumor.

Computational Model based Approach to Analyse Calcium (Ca2+) Channel in Ventricular Cells for Normal and Cardiac Arrhythmias Using Euler Integration Method – A Simulation Study

Aim: In this paper, analysis of ventricular arrhythmias are made with respect to the Calcium (Ca2+) ion channel dysfunction (generating improper electrical activity). Many cases can make arrhythmias and most of them are related to generation or conduction of Action Potential (AP) in cardiac myocardium. Materials and method: Human ventricular cell based on the model of the human endocardial cell by Ten Tusscher (TT). The TT model data is modified based on the experimental data of Han, describing the properties of Ca2+ currents and its channel dynamics in human ventricular cells. Euler integration method is used to analyse the human ventricular model for different channel failure conditions in the same group of 50 samples. Results: Our research findings focus with respect to normal and deviant Ca2+ conductance (GCaL). The normal GCaL 0.000175nS and deviant GCaL increase like (10%=0.000218nS, 25%=0.000182nS, 50%=0.000262nS and 100%=0.000350nS) having the normal AP average value ranges between 26.0mV to -74.0mV and 12.0mV to -88.0mV for 10% GCaL, 18.0mV to -78.0mV for 25% GCaL, 18.0mV to -78.0mV for 50% GCaL and 21.0mV to -75.0mV for 100% GCaL deviants. Similarly, deviant GCaL decrease like (10%=0.000158nS, 25%=0.000131nS, 50%=0.000088nS and 100%=0.000001nS) having the deviant AP mean values ranges between 10.0mV to -90.0mV for 10% GCaL, 7.0mV to -92.0mV for 25% GCaL, -9.0mV to -96.0mV for 50% GCaL and -51.0mV to 100.0mV for 100% GCaL. Simultaneously its membrane Ca2+ currents are having significant variations. Conclusion: The results show clearly for the affirmation for Excitation and Coupling (EC) failures. EC failures lead to a systole phase that is more prolonged, that in turns to produce QT syndrome and hypertrophic cardiomyopathy.

Antiepileptic Drug Tiagabine Does Not Directly Target Key Cardiac Ion Channels Kv11.1, Nav1.5 and Cav1.2.

Tiagabine is an antiepileptic drug used for the treatment of partial seizures in humans. Recently, this drug has been found useful in several non-epileptic conditions, including anxiety, chronic pain and sleep disorders. Since tachycardia—an impairment of cardiac rhythm due to cardiac ion channel dysfunction—is one of the most commonly reported non-neurological adverse effects of this drug, in the present paper we have undertaken pharmacological and numerical studies to assess a potential cardiovascular risk associated with the use of tiagabine. A chemical interaction of tiagabine with a model of human voltage-gated ion channels (VGICs) is described using the molecular docking method. The obtained in silico results imply that the adverse effects reported so far in the clinical cardiological of tiagabine could not be directly attributed to its interactions with VGICs. This is also confirmed by the results from the isolated organ studies (i.e., calcium entry blocking properties test) and in vivo (electrocardiogram study) assays of the present research. It was found that tachycardia and other tiagabine-induced cardiac complications are not due to a direct effect of this drug on ventricular depolarization and repolarization.

When Your Thyroid Causes Muscle Paralysis

Background: Periodic paralysis represents a spectrum of disorders characterized by ion channel dysfunction, mainly Na-K-ATPase channels. Thyrotoxic periodic paralysis (TTP) is defined by the presence of hypokalemia and diffuse muscular paralysis in a pre-existing hyperthyroid state. Diagnosis can be challenging, especially in cases of undiagnosed hyperthyroidism due to the non-specific presentation of this illness. We present a case of a young male who presented with recurrent, spontaneous paralysis found to have Graves’ disease. Clinical Case: A 38-year-old Asian male presented with sudden onset diffuse weakness, numbness, and tingling. The weakness was so severe that he could barely walk more than a few steps. However, his symptoms resolved in less than 24 hours without any intervention. Five months later, the patient experienced a recurrent episode of this similar constellation of diffuse muscle weakness and paresthesia. The patient was taken to a nearby hospital, where he was provided with intravenous fluid resuscitation. Initial laboratory workup was notable for hypokalemia to 1.4 mmol/L (n: 3.6 - 5.3 mmol/L), hypophosphatemia to 0.6 mmol/L (n: 2.4 – 4.8 mmol/L), and elevated creatinine kinase to 807 U/L (n: 22 – 198 U/L). Additionally, TSH was <0.001 mU/L (n: 0.45 – 4.5 mU/L) along with free T4 3.4 ng/dL (n: 0.80 – 1.70 ng/dL. The patient denied any other symptoms or a family history of similar symptoms. Lumbar puncture and brain/spine MRIs were unremarkable. Symptoms gradually improved throughout hospitalization with fluid and electrolyte repletion. Hyperthyroidism was treated with methimazole 5mg twice daily, later changed to PTU 50mg every eight hours due to recurrent headaches. Thyroid uptake scan showed diffuse bilateral uptake to 39.11% at 4 hours and 61.8% at 24 hours. Follow up labs revealed: TSH 0.3 mU/L, free T4 1.44 ng/dL, free T3 3.5 pg/mL (n: 2.3 – 4.1 pg/mL). Patient denied recurrent episodes of weakness or paresthesia. Definitive hyperthyroidism treatment with RAI was planned. Conclusions: The prevalence of TPP is higher in Asian males compared to other ethnic groups. TPP manifests as a sporadic onset of muscle weakness ranging from mild weakness to flaccid paralysis. It has been described that thyroid hormone itself augments the activity of the Na-K-ATPase channel and increases its responsiveness to beta-adrenergic stimulation. In addition, hyperthyroidism is associated with insulin resistance leading to hyperinsulinemia. Both beta-agonism and insulin promote potassium to be driven into cells resulting in hypokalemia. As such, activities which increase beta adrenergic stimulation, like stress and exercise, and promote the secretion of insulin, such as heavy carbohydrate intake, are well described triggers of TPP. Treatment revolves around acutely treating hypokalemia followed by preventing subsequent attacks via regulation of the altered thyroid state.

Channelopathies in fragile X syndrome.

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and the leading monogenic cause of autism. The condition stems from loss of fragile X mental retardation protein (FMRP), which regulates a wide range of ion channels via translational control, protein-protein interactions and second messenger pathways. Rapidly increasing evidence demonstrates that loss of FMRP leads to numerous ion channel dysfunctions (that is, channelopathies), which in turn contribute significantly to FXS pathophysiology. Consistent with this, pharmacological or genetic interventions that target dysregulated ion channels effectively restore neuronal excitability, synaptic function and behavioural phenotypes in FXS animal models. Recent studies further support a role for direct and rapid FMRP-channel interactions in regulating ion channel function. This Review lays out the current state of knowledge in the field regarding channelopathies and the pathogenesis of FXS, including promising therapeutic implications.

From Genotype to Phenotype: Expanding the Clinical Spectrum of CACNA1A Variants in the Era of Next Generation Sequencing.

Ion channel dysfunction is a key pathological substrate of episodic neurological disorders. A classical gene associated to paroxysmal movement disorders is CACNA1A, which codes for the pore-forming subunit of the neuronal calcium channel P/Q. Non-polyglutamine CACNA1A variants underlie familial hemiplegic ataxia type 1 (FHM1) and episodic ataxia type 2 (EA2). Classical paroxysmal manifestations of FHM1 are migraine attacks preceded by motor aura consisting of hemiparesis, aphasia, and disturbances of consciousness until coma. Patients with EA2 suffer of recurrent episodes of vertigo, unbalance, diplopia, and vomiting. Beyond these typical presentations, several reports highlighted manifold clinical features associated with P/Q channelopathies, from chronic progressive cerebellar ataxia to epilepsy and psychiatric disturbances. These manifestations may often outlast the burden of classical episodic symptoms leading to pitfalls in the diagnostic work-up. Lately, the spreading of next generation sequencing techniques linked de novo CACNA1A variants to an even broader phenotypic spectrum including early developmental delay, autism spectrum disorders, epileptic encephalopathy, and early onset paroxysmal dystonia. The age-dependency represents a striking new aspect of these phenotypes und highlights a pivotal role for P/Q channels in the development of the central nervous system in a defined time window. While several reviews addressed the clinical presentation and treatment of FHM1 and EA2, an overview of the newly described age-dependent manifestations is lacking. In this Mini-Review we present a clinical update, delineate genotype-phenotype correlations as well as summarize evidence on the pathophysiological mechanisms underlying the expanded phenotype associated with CACNA1A variants.

Pharmacological Approaches for the Modulation of the Potassium Channel KV4.x and KChIPs.

Ion channels are macromolecular complexes present in the plasma membrane and intracellular organelles of cells. Dysfunction of ion channels results in a group of disorders named channelopathies, which represent an extraordinary challenge for study and treatment. In this review, we will focus on voltage-gated potassium channels (KV), specifically on the KV4-family. The activation of these channels generates outward currents operating at subthreshold membrane potentials as recorded from myocardial cells (ITO, transient outward current) and from the somata of hippocampal neurons (ISA). In the heart, KV4 dysfunctions are related to Brugada syndrome, atrial fibrillation, hypertrophy, and heart failure. In hippocampus, KV4.x channelopathies are linked to schizophrenia, epilepsy, and Alzheimer’s disease. KV4.x channels need to assemble with other accessory subunits (β) to fully reproduce the ITO and ISA currents. β Subunits affect channel gating and/or the traffic to the plasma membrane, and their dysfunctions may influence channel pharmacology. Among KV4 regulatory subunits, this review aims to analyze the KV4/KChIPs interaction and the effect of small molecule KChIP ligands in the A-type currents generated by the modulation of the KV4/KChIP channel complex. Knowledge gained from structural and functional studies using activators or inhibitors of the potassium current mediated by KV4/KChIPs will better help understand the underlying mechanism involving KV4-mediated-channelopathies, establishing the foundations for drug discovery, and hence their treatments.

Long QT syndrome - Bench to bedside.

Long QT syndrome (LQTS) is a cardiovascular disorder characterized by an abnormality in cardiac repolarization leading to a prolonged QT interval and T-wave irregularities on the surface electrocardiogram. It is commonly associated with syncope, seizures, susceptibility to torsades de pointes, and risk for sudden death. LQTS is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. The availability of therapy for this lethal disease emphasizes the importance of early and accurate diagnosis. Additionally, understanding of the molecular mechanisms underlying LQTS could help to optimize genotype-specific treatments to prevent deaths in LQTS patients.In this review, we briefly summarize current knowledge regarding molecular underpinning of LQTS, in particular focusing on LQT1, LQT2, and LQT3, and discuss novel strategies to study ion channel dysfunction and drug-specific therapies in LQT1, LQT2, and LQT3 syndromes.

Enhancing glucose metabolism via gluconeogenesis is therapeutic in a zebrafish model of Dravet syndrome.

Energy-producing pathways are novel therapeutic targets for the treatment of neurodevelopmental disorders. Here, we focussed on correcting metabolic defects in a catastrophic paediatric epilepsy, Dravet syndrome which is caused by mutations in sodium channel NaV1.1 gene, SCN1A. We utilized a translatable zebrafish model of Dravet syndrome (scn1lab) which exhibits key characteristics of patients with Dravet syndrome and shows metabolic deficits accompanied by down-regulation of gluconeogenesis genes, pck1 and pck2. Using a metabolism-based small library screen, we identified compounds that increased gluconeogenesis via up-regulation of pck1 gene expression in scn1lab larvae. Treatment with PK11195, a pck1 activator and a translocator protein ligand, normalized dys-regulated glucose levels, metabolic deficits, translocator protein expression and significantly decreased electrographic seizures in mutant larvae. Inhibition of pck1 in wild-type larvae mimicked metabolic and behaviour defects observed in scn1lab mutants. Together, this suggests that correcting dys-regulated metabolic pathways can be therapeutic in neurodevelopmental disorders such as Dravet syndrome arising from ion channel dysfunction.

The study of sodium and potassium channel gene single-nucleotide variation significance in non-mechanical forms of epilepsy

BackgroundEpilepsy is one of the most common and heterogeneous neurological diseases. The main clinical signs of the disease are repeated symptomatic or idiopathic epileptic seizures of both convulsive and non-convulsive nature that develop against a background of lost or preserved consciousness. The genetic component plays a large role in the etiology of idiopathic forms of epilepsy. The study of the molecular genetic basis of neurological disorders has led to a rapidly growing number of gene mutations known to be involved in hereditary ion channel dysfunction. The aim of this research was to evaluate the involvement of single-nucleotide variants that modify the function of genes (SCN1A, KCNT1, KCNTС1, and KCNQ2) encoding sodium and potassium ion channel polypeptides in the development of epilepsy.ResultsDe novo mutations in the sodium channel gene SCN1A c.5347G>A (p. Ala1783Thr) were detected in two patients with Dravet syndrome, with a deletion in exon 26 found in one. Three de novo mutations in the potassium channel gene KCNT1 c.2800G>A (p. Ala934Thr), were observed in two patients with temporal lobe epilepsy (TLE) and one patient with residual encephalopathy. Moreover, a control cohort matched to the case cohort did not reveal any SNVs among conditionally healthy individuals, supporting the pathogenic significance of the studied SNVs.ConclusionOur results are supported by literature data showing that the sodium ion channel gene SCN1A c.5347G>A mutation may be involved in the pathogenesis of Dravet syndrome. We also note that the c.2800G>A mutation in the potassium channel gene KCNT1 can cause not only autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) but also other forms of epilepsy. To treat pathogenetic mutations that accelerate the function of sodium and potassium ion channels, we recommend ion channel blockade drug therapy.

Post-operative Atrial Fibrillation at the Start of Atrial Fibrillation Burden

Atrial Fibrillation (AF) is the most common persistent arrhythmia with adverse clinical outcomes. AF ectopic firing and re-entry depends on several mechanisms: (1) ion channel dysfunction; (2) Ca2+-handling abnormalities; (3) structural remodelling; (4) autonomic neural dysregulation. The oxidized CAMKII enzyme pathway establishes a connexion between redox imbalance and the electrical and functional cardiomyocyte properties altered in AF patients. Postoperative atrial fibrillation (PoAF) is the most common complication after cardiac surgery and a subtype of AF, associated with increased time spent in the intensive care unit (ICU), in-hospital stay, stroke incidence and 30-day and long-term mortality. Recent studies have implicated oxidative stress in AF pathophysiology including mechanisms such as an imbalance in reactive oxygen species (ROS) production, decreased endothelial nitric oxide synthase (eNOS) activity and nitric oxide unavailability. Indeed, NADPH oxidase enzymes (NOX) are largely responsible for this imbalance, which is supported by the beneficial effect of statins in early atrium electrical remodelling. Epicardial adipose tissue has a direct contact with the myocardium, located between the myocardium and visceral pericardium, and it has been established a clinical relationship between EAT and the development of AF. In this review, we explore pathophysiological mechanisms of AF and POAF, as well as its implications for management.

The clinical and genetic heterogeneity analysis of five families with primary periodic paralysis

ABSTRACT To explore the clinical and genetic characteristics of five families with primary periodic paralysis (PPP). We reviewed clinical manifestations, laboratory results, electrocardiogram, electromyography, muscle biopsy, and genetic analysis from five families with PPP. Five families with PPP included: hypokalemic periodic paralysis type 1 (HypoPP1, CACNA1S, 1/5), hypokalemic periodic paralysis type 2 (HypoPP2, SCN4A, 2/5), normokalemic periodic paralysis (NormoPP, SCN4A, 1/5), and Andersen-Tawil syndrome (ATS, KCNJ2, 1/5). The basic clinical manifestations of five families were consistent with PPP, presenting with paroxysmal muscle weakness, with or without abnormal serum potassium. ATS was accompanied by ventricular arrhythmias, and skeletal and craniofacial anomalies, developing with a permanent fixed myopathy later. The electromyography showed diffuse myopathic discharge, and muscle biopsy showed tubular aggregates. Genetic testing revealed five families with PPP carried CACNA1S (R1242S), SCN4A (R675Q, T704M), and KCNJ2 (R218Q) respectively. The novel heterozygous R1242S mutation in CACNA1S caused a conformational change in the protein structure, and the amino acid of this mutation site was highly conserved among different species. SCN4A mutations led to two phenotypes of HypoPP2 and NormoPP. PPPs are autosomal dominant disorders of ion channel dysfunction characterized by episodic flaccid muscle weakness secondary to abnormal sarcolemmal excitability. PPPs are caused by mutations in skeletal muscle calcium channel CaV1.1 gene (CACNA1S), sodium channel NaV1.4 gene (SCN4A), and potassium channels Kir2.1, Kir3.4 genes (KCNJ2, KCNJ5), including HypoPP1, HypoPP2, NormoPP, HyperPP, and ATS, which have significant clinical and genetic heterogeneity. Diagnosis is based on the characteristic clinical presentation then confirmed by genetic testing.

A WaveNet based Ion Channel prediction Method

There are many diseases associated with the dysfunction of ion channels. Ion channels are a class of proteins embedded in cell membranes that serve principle physiological functions such as memorization, learning and pain signaling. In order to help scientists learn more about ion channels and how they cause diseases, a team in Liverpool University published a public dataset about Ion channels. This paper presents a Wavenet based model to predict the number of Ion channels open at each time point. Wavenet is a type of deep neural network designed for one-dimensional signals. We used the Kalman filter to denoise the original signals and compared WaveNet with classical machine learning methods like SVM and Naïve Bayes to show the superior performance of the WaveNet model.

Identification of a SCN4A mutation in a large Chinese family with atypical normokalemic periodic paralysis using whole-exome sequencing.

ObjectivesNormokalemic periodic paralysis (NormoKPP) of skeletal muscle is an autosomal dominant disorder caused by mutations in the gene encoding voltage-gated sodium channel protein type 4 subunit alpha (SCN4A), which leads to ion channel dysfunction. Little is known about the relationship between genotype and the clinical symptoms of NormoKPP. The present study aimed to evaluate the genetic variation in a large Chinese family with NormoKPP. The patients in this pedigree did not respond to saline treatment, but calcium gluconate treatment was effective.MethodsWe performed a series of clinical examinations and genetic analyses, using whole-exome and Sanger sequencing, to examine the mutation status of SCN4A in a Chinese family segregating for NormoKPP.ResultsWhole-exome sequencing revealed a c.2111C>T substitution in SCN4A in most of the affected family members. This mutation results in the amino acid substitution p.T704M.ConclusionsThese results support a causative role of this mutation in SCN4A in NormoKPP, and provide information about the relationship between genotype and atypical clinical symptoms.

Genetics and Epigenetics of Atrial Fibrillation.

Atrial fibrillation (AF) is known to be the most common supraventricular arrhythmia affecting up to 1% of the general population. Its prevalence exponentially increases with age and could reach up to 8% in the elderly population. The management of AF is a complex issue that is addressed by extensive ongoing basic and clinical research. AF centers around different types of disturbances, including ion channel dysfunction, Ca2+-handling abnormalities, and structural remodeling. Genome-wide association studies (GWAS) have uncovered over 100 genetic loci associated with AF. Most of these loci point to ion channels, distinct cardiac-enriched transcription factors, as well as to other regulatory genes. Recently, the discovery of post-transcriptional regulatory mechanisms, involving non-coding RNAs (especially microRNAs), DNA methylation, and histone modification, has allowed to decipher how a normal heart develops and which modifications are involved in reshaping the processes leading to arrhythmias. This review aims to provide a current state of the field regarding the identification and functional characterization of AF-related epigenetic regulatory networks

Myelin protein zero gene dose dependent axonal ion-channel dysfunction in a family with Charcot-Marie-Tooth disease

ObjectiveThe myelin impairment in demyelinating Charcot-Marie-Tooth (CMT) disease leads to various degrees of axonal degeneration, the ultimate cause of disability. We aimed to assess the pathophysiological changes in axonal function related to the neuropathy severity in hypo-/demyelinating CMT patients associated with myelin protein zero gene (MPZ) deficiency. MethodsWe investigated four family members (two parents and two sons) harboring a frameshift mutation (c.306delA, p.Asp104ThrfsTer14) in the MPZ gene, predicted to result in a nonfunctional P0, by conventional conduction studies and multiple measures of motor axon excitability. In addition to the conventional excitability studies of the median nerve at the wrist, we tested the spinal accessory nerves. Control measures were obtained from 14 healthy volunteers. ResultsThe heterozygous parents (aged 56 and 63) had a mild CMT1B whereas their two homozygous sons (aged 31 and 39 years) had a severe Dejerine-Sottas disease phenotype. The spinal accessory nerve excitability could be measured in all patients. The sons showed reduced deviations during depolarizing threshold electrotonus and other depolarizing features which were not apparent in the accessory and median nerve studies of the parents. Mathematical modeling indicated impairment in voltage-gated sodium channels. This interpretation was supported by comparative modeling of excitability measurements in MPZ deficient mice. ConclusionOur data suggest that axonal depolarization in the context of abnormal voltage-gated sodium channels precedes axonal degeneration in severely hypo-/demyelinating CMT as previously reported in the mouse models. SignificanceMeasures of the accessory nerve excitability could provide pathophysiological markers of neurotoxicity in severe demyelinating neuropathies.

Atrial fibrillation in horses part 1: Pathophysiology

Atrial fibrillation (AF) is the most common clinically relevant arrhythmia in horses, with a reported prevalence up to 2.5%. The pathophysiology has mainly been investigated in experimental animal models and human medicine, with limited studies in horses. Atrial fibrillation results from the interplay between electrical triggers and a susceptible substrate. Triggers consist of atrial premature depolarizations due to altered automaticity or triggered activity, or local (micro)reentry. The arrhythmia is promoted by atrial myocardial ion channel alterations, Ca2+ handling alterations, structural abnormalities, and autonomic nervous system imbalance. Predisposing factors include structural heart disease such as valvular regurgitation resulting in chronic atrial stretch, although many horses show so-called ‘lone AF’ or idiopathic AF in which no underlying cardiac abnormalities can be detected using routine diagnostic techniques. These horses may have underlying ion channel dysfunction or undiagnosed myocardial (micro)structural alterations. Atrial fibrillation itself results in electrical, contractile and structural remodelling, fostering AF maintenance. Electrical remodelling leads to shortening of the atrial effective refractory period, promoting reentry. Contractile remodelling consists of decreased myocardial contractility, while structural remodelling includes the development of interstitial fibrosis and atrial enlargement. Reverse remodelling occurs after cardioversion to sinus rhythm, but full recovery may take weeks to months depending on duration of AF. The clinical signs of AF depend on the aerobic demands during exercise, ventricular rhythm response and presence of underlying cardiac disease. In horses with so-called ‘lone AF’, clinical signs are usually absent at rest but during exercise poor performance, exercise-induced pulmonary hemorrhage, respiratory distress, weakness or rarely collapse may develop.

Urinary bladder smooth muscle ion channels: expression, function, and regulation in health and disease.

Urinary bladder smooth muscle (UBSM), also known as detrusor smooth muscle, forms the bladder wall and ultimately determines the two main attributes of the organ: urine storage and voiding. The two functions are facilitated by UBSM relaxation and contraction, respectively, which depend on UBSM excitability shaped by multiple ion channels. In this review, we summarize the current understanding of key ion channels establishing and regulating UBSM excitability and contractility. They include excitation-enhancing voltage-gated Ca2+ (Cav) and transient receptor potential channels, excitation-reducing K+ channels, and still poorly understood Cl- channels. Dynamic interplay among UBSM ion channels determines the overall level of Cav channel activity. The net Ca2+ influx via Cav channels increases global intracellular Ca2+ concentration, which subsequently triggers UBSM contractility. Here, for each ion channel type, we describe UBSM tissue/cell expression (mRNA and protein) profiles and their role in regulating excitability and contractility of UBSM in various animal species, including the mouse, rat, and guinea pig, and, most importantly, humans. The currently available data reveal certain interspecies differences, which complicate the translational value of published animal research results to humans. This review highlights recent developments, findings on genetic knockout models, pharmacological data, reports on UBSM ion channel dysfunction in animal bladder disease models, and the very limited human studies currently available. Among all gaps in present-day knowledge, the unknowns on expression and functional roles for ion channels determined directly in human UBSM tissues and cells under both normal and disease conditions remain key hurdles in the field.