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.

Cardiac function is regulated by the sodium-dependent inhibition of the sodium-calcium exchanger NCX1.

The Na-Ca exchanger (NCX1) is the dominant Ca extrusion mechanism in cardiac myocytes. NCX1 activity is inhibited by intracellular Na via a process known as Na-dependent inactivation. A central question is whether this inactivation plays a physiological role in heart function.

Decreased Left Atrial Cardiomyocyte FGF13 Expression Increases Vulnerability to Postoperative Atrial Fibrillation in Humans.

Postoperative atrial fibrillation (POAF) is the most common complication after cardiac surgery and a significant cause of increased morbidity and mortality. The development of novel POAF therapeutics has been limited by an insufficient understanding of molecular mechanisms promoting atrial fibrillation. In this observational cohort study, we enrolled 28 patients without a history of atrial fibrillation that underwent mitral valve surgery for degenerative mitral regurgitation and obtained left atrial tissue samples along the standard atriotomy incision in proximity to the right pulmonary veins.

Fibroblasts in heart scar tissue directly regulate cardiac excitability and arrhythmogenesis.

After heart injury, dead heart muscle is replaced by scar tissue. Fibroblasts can electrically couple with myocytes, and changes in fibroblast membrane potential can lead to myocyte excitability, which suggests that fibroblast-myocyte coupling in scar tissue may be responsible for arrhythmogenesis. However, the physiologic relevance of electrical coupling of myocytes and fibroblasts and its impact on cardiac excitability in vivo have never been demonstrated.

Myocardial fibrosis and calcification are attenuated by microRNA-129-5p targeting Asporin and Sox9 in cardiac fibroblasts.

Myocardial fibrosis and calcification associate with adverse outcomes in nonischemic heart failure. Cardiac fibroblasts (CF) transition into myofibroblasts (MF) and osteogenic fibroblasts (OF) to promote myocardial fibrosis and calcification. However, common upstream mechanisms regulating both CF-to-MF transition and CF-to-OF transition remain unknown.

Activation of Endothelial Large Conductance Potassium Channels Protects against TNF-α-Induced Inflammation.

Elevated TNF-α levels in serum and broncho-alveolar lavage fluid of acute lung injury patients correlate with mortality rates. We hypothesized that pharmacological plasma membrane potential (Em) hyperpolarization protects against TNF-α-induced CCL-2 and IL-6 secretion from human pulmonary endothelial cells through inhibition of inflammatory Ca-dependent MAPK pathways. Since the role of Ca influx in TNF-α-mediated inflammation remains poorly understood, we explored the role of L-type voltage-gated Ca (Ca) channels in TNF-α-induced CCL-2 and IL-6 secretion from human pulmonary endothelial cells.

Activation of TREK-1 () potassium channels protects against influenza A-induced lung injury.

Influenza-A virus (IAV) infects yearly an estimated one billion people worldwide, resulting in 300,000-650,000 deaths. Preventive vaccination programs and antiviral medications represent the mainstay of therapy, but with unacceptably high morbidity and mortality rates, new targeted therapeutic approaches are urgently needed. Since inflammatory processes are commonly associated with measurable changes in the cell membrane potential (Em), we investigated whether Em hyperpolarization via TREK-1 () K channel activation can protect against influenza-A virus (IAV)-induced pneumonia.

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.

R-on-T and the initiation of reentry revisited: Integrating old and new concepts.

Initiation of reentry requires 2 factors: (1) a triggering event, most commonly focal excitations such as premature ventricular complexes (PVCs); and (2) a vulnerable substrate with regional dispersion of refractoriness and/or excitability, such as occurs during the T wave of the electrocardiogram when some areas of the ventricle have repolarized and recovered excitability but others have not. When the R wave of a PVC coincides in time with the T wave of the previous beat, this timing can lead to unidirectional block and initiation of reentry, known as the R-on-T phenomenon. Classically, the PVC triggering reentry has been viewed as arising focally from 1 region and propagating into another region whose recovery is delayed, resulting in unidirectional conduction block and reentry initiation.

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.

The distinct role of the four voltage sensors of the skeletal CaV1.1 channel in voltage-dependent activation.

Initiation of skeletal muscle contraction is triggered by rapid activation of RYR1 channels in response to sarcolemmal depolarization. RYR1 is intracellular and has no voltage-sensing structures, but it is coupled with the voltage-sensing apparatus of CaV1.1 channels to inherit voltage sensitivity.

K2.1 (TREK-1) potassium channel activation protects against hyperoxia-induced lung injury.

No targeted therapies exist to counteract Hyperoxia (HO)-induced Acute Lung Injury (HALI). We previously found that HO downregulates alveolar K2.1 (TREK-1) K channels, which results in worsening lung injury.

BK Channels Regulate LPS-induced CCL-2 Release from Human Pulmonary Endothelial Cells.

We recently established a role for the stretch-activated two-pore-domain K (K2P) channel TREK-1 (K2P2.1) in inflammatory cytokine secretion using models of hyperoxia-, mechanical stretch-, and TNF-α-induced acute lung injury. We have now discovered the expression of large conductance, Ca-activated K (BK) channels in human pulmonary microvascular endothelial cells and primary human alveolar epithelial cells using semiquantitative real-time PCR, IP and Western blot, and investigated their role in inflammatory cytokine secretion using an LPS-induced acute lung injury model.

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.

Small-conductance Ca-activated K channels promote J-wave syndrome and phase 2 reentry.

Background: Small-conductance Ca-activated potassium (SK) channels play complex roles in cardiac arrhythmogenesis. SK channels colocalize with L-type Ca channels, yet how this colocalization affects cardiac arrhythmogenesis is unknown.

Objective: The purpose of this study was to investigate the role of colocalization of SK channels with L-type Ca channels in promoting J-wave syndrome and ventricular arrhythmias.

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.

MitoBK channel is functionally associated with its regulatory β1 subunit in cardiac mitochondria.

Key Points: Association of plasma membrane BK channels with BK-β subunits shapes their biophysical properties and physiological roles; however, functional modulation of the mitochondrial BK channel (mitoBK ) by BK-β subunits is not established. MitoBK -α and the regulatory BK-β1 subunit associate in mouse cardiac mitochondria. A large fraction of mitoBK display properties similar to that of plasma membrane BK when associated with BK-β1 (left-shifted voltage dependence of activation, V  = -55 mV, 12 µm matrix Ca ).

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.

Molecular determinants of pH regulation in the cardiac Na-Ca exchanger.

The cardiac Na-Ca exchanger (NCX) plays a critical role in the heart by extruding Ca after each contraction and thus regulates cardiac contractility. The activity of NCX is strongly inhibited by cytosolic protons, which suggests that intracellular acidification will have important effects on heart contractility. However, the mechanisms underlying this inhibition remain elusive.

Hyperoxia treatment of TREK-1/TREK-2/TRAAK-deficient mice is associated with a reduction in surfactant proteins.

We previously proposed a role for the two-pore domain potassium (K2P) channel TREK-1 in hyperoxia (HO)-induced lung injury. To determine whether redundancy among the three TREK isoforms (TREK-1, TREK-2, and TRAAK) could protect from HO-induced injury, we now examined the effect of deletion of all three TREK isoforms in a clinically relevant scenario of prolonged HO exposure and mechanical ventilation (MV). We exposed WT and TREK-1/TREK-2/TRAAK-deficient [triple knockout (KO)] mice to either room air, 72-h HO, MV [high and low tidal volume (TV)], or a combination of HO + MV and measured quasistatic lung compliance, bronchoalveolar lavage (BAL) protein concentration, histologic lung injury scores (LIS), cellular apoptosis, and cytokine levels.