Worldwide Sodium Channel Conference, January 31st-February 2nd, 2024, Grindelwald, Switzerland.

The following is a brief report of the inaugural Worldwide Sodium Channels Conference, held in Grindelwald, Switzerland, in January 2024. This excellent in-person conference followed the highly successful online Worldwide Sodium Channel Seminars series which started following the COVID-19 pandemic, in 2021. We present here our highlights of the 45 presentations delivered over the two-and-a-half-day conference, focusing on key outputs from each of the eight sessions.

A Rich Conformational Palette Underlies Human Ca2.1-Channel Availability.

Depolarization-evoked opening of Ca2.1 (P/Q-type) Ca-channels triggers neurotransmitter release, while voltage-dependent inactivation (VDI) limits channel availability to open, contributing to synaptic plasticity. The mechanism of Ca2.

Voltage-dependent G-protein regulation of Ca2.2 (N-type) channels.

How G proteins inhibit N-type, voltage-gated, calcium-selective channels (Ca2.2) during presynaptic inhibition is a decades-old question. G proteins Gβγ bind to intracellular Ca2.

Electrical and G-protein Regulation of CaV2.2 (N-type) Channels.

How G-proteins inhibit N-type, voltage-gated, calcium-selective channels (Ca 2.2) during presynaptic inhibition is a decades-old question. G-proteins Gβγ bind to intracellular Ca 2.

Two epilepsy-associated variants in KCNA2 (K 1.2) at position H310 oppositely affect channel functional expression.

Two KCNA2 variants (p.H310Y and p.H310R) were discovered in paediatric patients with epilepsy and developmental delay.

Circadian and Seasonal Pattern of Arrhythmic Events in Arrhythmogenic Cardiomyopathy Patients.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disease associated with an increased risk of life-threatening arrhythmias. The aim of the present study was to evaluate the association of ventricular arrhythmias (VA) with circadian and seasonal variation in ARVC. One hundred two ARVC patients with an implantable cardioverter defibrillator (ICD) were enrolled in the study.

An epilepsy-associated K1.2 charge-transfer-center mutation impairs K1.2 and K1.4 trafficking.

We report on a heterozygous KCNA2 variant in a child with epilepsy. KCNA2 encodes KV1.2 subunits, which form homotetrameric potassium channels and participate in heterotetrameric channel complexes with other KV1-family subunits, regulating neuronal excitability.

Suppression of ventricular arrhythmias by targeting late L-type Ca2+ current.

Ventricular arrhythmias, a leading cause of sudden cardiac death, can be triggered by cardiomyocyte early afterdepolarizations (EADs). EADs can result from an abnormal late activation of L-type Ca2+ channels (LTCCs). Current LTCC blockers (class IV antiarrhythmics), while effective at suppressing EADs, block both early and late components of ICa,L, compromising inotropy.

Diagnostic and Prognostic Value of Cardiovascular Magnetic Resonance in Neuromuscular Cardiomyopathies.

Neuromuscular diseases (NMD) encompass a broad spectrum of diseases with variable type of cardiac involvement and there is lack of clinical data on Cardiovascular Magnetic Resonance (CMR) phenotypes or even prognostic value of CMR in NMD. We explored the diagnostic and prognostic value of CMR in NMD-related cardiomyopathies. The study included retrospective analysis of a cohort of 111 patients with various forms of NMD; mitochondrial: n = 14, Friedreich's ataxia (FA): n = 27, myotonic dystrophy: n = 27, Becker/Duchenne's muscular dystrophy (BMD/DMD): n = 15, Duchenne's carriers: n = 6, other: n = 22.

Tracking the motion of the K1.2 voltage sensor reveals the molecular perturbations caused by a de novo mutation in a case of epilepsy.

Key Points: K1.2 channels, encoded by the KCNA2 gene, regulate neuronal excitability by conducting K upon depolarization. A new KCNA2 missense variant was discovered in a patient with epilepsy, causing amino acid substitution F302L at helix S4, in the K1.

Antithrombotic Treatment in Cardiomyopathies.

Cardiomyopathies are a heterogeneous group of heart muscle diseases and important cause of heart failure with reduced or preserved ejection fraction. Although there is an increasing body of evidence on the incidence, pathophysiology, and natural history of heart failure (HF) in cardiomyopathies, certain aspects of the therapeutic strategies remain unclear. More particularly, there is no consensus if to whether antithrombotic therapy has a favorable risk: benefit ratio in reducing thromboembolic event rate in patients with cardiomyopathies without suffering from primary valvular disease or atrial fibrillation.

Circuit-Specific Early Impairment of Proprioceptive Sensory Neurons in the SOD1 Mouse Model for ALS.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which motor neurons degenerate, resulting in muscle atrophy, paralysis, and fatality. Studies using mouse models of ALS indicate a protracted period of disease development with progressive motor neuron pathology, evident as early as embryonic and postnatal stages. Key missing information includes concomitant alterations in the sensorimotor circuit essential for normal development and function of the neuromuscular system.

Resurgent Na+ Current Offers Noise Modulation in Bursting Neurons.

Neurons utilize bursts of action potentials as an efficient and reliable way to encode information. It is likely that the intrinsic membrane properties of neurons involved in burst generation may also participate in preserving its temporal features. Here we examined the contribution of the persistent and resurgent components of voltage-gated Na+ currents in modulating the burst discharge in sensory neurons.

Risk score for the exclusion of arrhythmic events in arrhythmogenic right ventricular cardiomyopathy at first presentation.

Aims: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically determined heart muscle disorder associated with an increased risk of life-threatening arrhythmias in some patients. Risk stratification remains challenging. Therefore, we sought a non-invasive, easily applicable risk score to predict sustained ventricular arrhythmias in these patients.

Heart failure in patients with arrhythmogenic right ventricular cardiomyopathy: Genetic characteristics.

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically determined heart muscle disorder. The incidence of heart failure (HF) in ARVC has been reported at 5-13%. We aimed to define the genotype and disease progression of ARVC patients with HF.

Harnessing photoinduced electron transfer to optically determine protein sub-nanoscale atomic distances.

Proteins possess a complex and dynamic structure, which is influenced by external signals and may change as they perform their biological functions. We present an optical approach, distance-encoding photoinduced electron transfer (DEPET), capable of the simultaneous study of protein structure and function. An alternative to FRET-based methods, DEPET is based on the quenching of small conjugated fluorophores by photoinduced electron transfer: a reaction that requires contact of the excited fluorophore with a suitable electron donor.

Arrhythmogenic right ventricular cardiomyopathy in Boxer dogs: the diagnosis as a link to the human disease.

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a myocardial disease with an increased risk for ventricular arrhythmias. The condition, which occurs in Boxer dogs, shares phenotypic features with the human disease arrhythmogenic cardiomyopathy (ACM) suggesting its potential as a natural animal model. However, there are currently no universally accepted clinical criteria to diagnose ARVC in Boxer dogs.

The α2δ-1 subunit remodels CaV1.2 voltage sensors and allows Ca2+ influx at physiological membrane potentials.

Excitation-evoked calcium influx across cellular membranes is strictly controlled by voltage-gated calcium channels (CaV), which possess four distinct voltage-sensing domains (VSDs) that direct the opening of a central pore. The energetic interactions between the VSDs and the pore are critical for tuning the channel's voltage dependence. The accessory α2δ-1 subunit is known to facilitate CaV1.

Targeting the late component of the cardiac L-type Ca2+ current to suppress early afterdepolarizations.

Early afterdepolarizations (EADs) associated with prolongation of the cardiac action potential (AP) can create heterogeneity of repolarization and premature extrasystoles, triggering focal and reentrant arrhythmias. Because the L-type Ca(2+) current (ICa,L) plays a key role in both AP prolongation and EAD formation, L-type Ca(2+) channels (LTCCs) represent a promising therapeutic target to normalize AP duration (APD) and suppress EADs and their arrhythmogenic consequences. We used the dynamic-clamp technique to systematically explore how the biophysical properties of LTCCs could be modified to normalize APD and suppress EADs without impairing excitation-contraction coupling.

Functional heterogeneity of the four voltage sensors of a human L-type calcium channel.

Excitation-evoked Ca(2+) influx is the fastest and most ubiquitous chemical trigger for cellular processes, including neurotransmitter release, muscle contraction, and gene expression. The voltage dependence and timing of Ca(2+) entry are thought to be functions of voltage-gated calcium (CaV) channels composed of a central pore regulated by four nonidentical voltage-sensing domains (VSDs I-IV). Currently, the individual voltage dependence and the contribution to pore opening of each VSD remain largely unknown.

The influence of aortoseptal angulation on provocable left ventricular outflow tract obstruction in hypertrophic cardiomyopathy.

Objectives: Aortoseptal angulation (AoSA) can predict provocable left ventricular outflow tract obstruction (LVOTO) in patients with symptomatic hypertrophic cardiomyopathy (HCM). Lack of a standardised measurement technique in HCM without the need for complex three-dimensional (3D) imaging limits its usefulness in routine clinical practice. This study aimed to validate a simple measurement of AoSA using 2D echocardiography and cardiac MR (CMR) imaging as a predictor of LVOTO.

Arrhythmogenic right ventricular cardiomyopathy mimics: role of cardiovascular magnetic resonance.

Background: Cardiovascular magnetic resonance (CMR) is commonly used in patients with suspected arrhythmogenic right ventricular cardiomyopathy (ARVC) based on ECG, echocardiogram and Holter. However, various diseases may present with clinical characteristics resembling ARVC causing diagnostic dilemmas. The aim of this study was to explore the role of CMR in the differential diagnosis of patients with suspected ARVC.

A validation study of the 2003 American College of Cardiology/European Society of Cardiology and 2011 American College of Cardiology Foundation/American Heart Association risk stratification and treatment algorithms for sudden cardiac death in patients with hypertrophic cardiomyopathy.

Aims: Sudden cardiac death (SCD) is a common mode of death in hypertrophic cardiomyopathy (HCM), but identification of patients who are at a high risk of SCD is challenging as current risk stratification guidelines have never been formally validated. The objective of this study was to assess the power of the 2003 American College of Cardiology (ACC)/European Society of Cardiology (ESC) and 2011 ACC Foundation (ACCF)/American Heart Association (AHA) SCD risk stratification algorithms to distinguish high risk patients who might be eligible for an implantable cardioverter defibrillator (ICD) from low risk individuals.

Methods And Results: We studied 1606 consecutively evaluated HCM patients in an observational, retrospective cohort study.

Recurrent missense mutations in TMEM43 (ARVD5) due to founder effects cause arrhythmogenic cardiomyopathies in the UK and Canada.

Aims: Autosomal dominant arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) (in the group of arrhythmogenic cardiomyopathies) is a common cause of sudden cardiac death in young adults. It is both clinically and genetically heterogeneous, with 12 loci (ARVC/D1-12) and eight genes identified, the majority of which encode structural proteins of cardiac desmosomes. The most recent gene identified, TMEM43, causes disease due to a missense mutation in a non-desmosomal gene (p.