Kir6.1, a component of an ATP-sensitive potassium channel, regulates natural killer cell development.

Introduction: Involved in immunity and reproduction, natural killer (NK) cells offer opportunities to develop new immunotherapies to treat infections and cancer or to alleviate pregnancy complications. Most current strategies use cytokines or antibodies to enhance NK-cell function, but none use ion channel modulators, which are widely used in clinical practice to treat hypertension, diabetes, epilepsy, and other conditions. Little is known about ion channels in NK cells.

Do K channels have a role in immunity?

Ion channels, exchangers and pumps are expressed ubiquitously in cells from all phyla of life. In mammals, their role is best described in excitable cells, where they regulate the initiation and propagation of action potentials. There are over 70 different types of K channels subunits that contribute to these processes.

Kir6.1, a component of an ATP-sensitive potassium channel, regulates natural killer cell development.

Involved in immunity and reproduction, natural killer (NK) cells offer opportunities to develop new immunotherapies to treat infections and cancer or to alleviate pregnancy complications. Most current strategies use cytokines or antibodies to enhance NK-cell function, but none use ion channel modulators, which are widely used in clinical practice to treat hypertension, diabetes, epilepsy, and other conditions. Little is known about ion channels in NK cells.

CL-705G: a novel chemical Kir6.2-specific K channel opener.

K channels have diverse roles, including regulation of insulin secretion and blood flow, and protection against biological stress responses and are excellent therapeutic targets. Different subclasses of K channels exist in various tissue types due to the unique assemblies of specific pore-forming (Kir6.x) and accessory (SURx) subunits.

The cardioprotective role of sirtuins is mediated in part by regulating K channel surface expression.

Sirtuins are NAD-dependent deacetylases with beneficial roles in conditions relevant to human health, including metabolic disease, type II diabetes, obesity, cancer, aging, neurodegenerative diseases, and cardiac ischemia. Since ATP-sensitive K (K) channels have cardioprotective roles, we investigated whether they are regulated by sirtuins. Nicotinamide mononucleotide (NMN) was used to increase cytosolic NAD levels and to activate sirtuins in cell lines, isolated rat and mouse cardiomyocytes or insulin-secreting INS-1 cells.

Rab35 GTPase positively regulates endocytic recycling of cardiac K channels.

ATP-sensitive K (K) channel couples membrane excitability to intracellular energy metabolism. Maintaining K channel surface expression is key to normal insulin secretion, blood pressure and cardioprotection. However, the molecular mechanisms regulating K channel internalization and endocytic recycling, which directly affect the surface expression of K channels, are poorly understood.

Subcellular trafficking and endocytic recycling of K channels.

Sarcolemmal/plasmalemmal ATP-sensitive K (K) channels have key roles in many cell types and tissues. Hundreds of studies have described how the K channel activity and ATP sensitivity can be regulated by changes in the cellular metabolic state, by receptor signaling pathways and by pharmacological interventions. These alterations in channel activity directly translate to alterations in cell or tissue function, that can range from modulating secretory responses, such as insulin release from pancreatic β-cells or neurotransmitters from neurons, to modulating contractile behavior of smooth muscle or cardiac cells to elicit alterations in blood flow or cardiac contractility.

The volume-regulated anion channel LRRC8C suppresses T cell function by regulating cyclic dinucleotide transport and STING-p53 signaling.

The volume-regulated anion channel (VRAC) is formed by LRRC8 proteins and is responsible for the regulatory volume decrease (RVD) after hypotonic cell swelling. Besides chloride, VRAC transports other molecules, for example, immunomodulatory cyclic dinucleotides (CDNs) including 2'3'cGAMP. Here, we identify LRRC8C as a critical component of VRAC in T cells, where its deletion abolishes VRAC currents and RVD.

Biliary tract anatomical variance - the value of MRCP.

Duplication of the common bile duct (CBD) is a rare congenital anomaly of the bile ducts that should be diagnosed prior to surgery in order to optimise management and prevent complications. We report a case of a patient presenting with choledocholithiasis and type Va duplicated extrahepatic bile duct that was missed on ultrasonography. The atypical course prompted further imaging with magnetic resonance cholangiopancreatography (MRCP), which identified the aberrant bile duct and assisted in safe preoperative and operative management.

Targeting Piezo1 unleashes innate immunity against cancer and infectious disease.

Piezo1 is a mechanosensitive ion channel that has gained recognition for its role in regulating diverse physiological processes. However, the influence of Piezo1 in inflammatory disease, including infection and tumor immunity, is not well studied. We postulated that Piezo1 links physical forces to immune regulation in myeloid cells.

A distinct molecular mechanism by which phenytoin rescues a novel long QT 3 variant.

Background: Genetic variants in SCN5A can result in channelopathies such as the long QT syndrome type 3 (LQT3), but the therapeutic response to Na channel blockers can vary. We previously reported a case of an infant with malignant LQT3 and a missense Q1475P SCN5A variant, who was effectively treated with phenytoin, but only partially with mexiletine. Here, we functionally characterized this variant and investigated possible mechanisms for the differential drug actions.

Palmitoylation of the K channel Kir6.2 subunit promotes channel opening by regulating PIP sensitivity.

A physiological role for long-chain acyl-CoA esters to activate ATP-sensitive K (K) channels is well established. Circulating palmitate is transported into cells and converted to palmitoyl-CoA, which is a substrate for palmitoylation. We found that palmitoyl-CoA, but not palmitic acid, activated the channel when applied acutely.

Ankyrin-G mediates targeting of both Na and K channels to the rat cardiac intercalated disc.

We investigated targeting mechanisms of Na and K channels to the intercalated disk (ICD) of cardiomyocytes. Patch clamp and surface biotinylation data show reciprocal downregulation of each other's surface density. Mutagenesis of the Kir6.

The effectiveness of Schroth exercises in adolescents with idiopathic scoliosis: A systematic review and meta-analysis.

Background: Adolescent idiopathic scoliosis (AIS) is one of the most common structural spinal deformities in adolescents, becoming apparent around the time of puberty. Schroth scoliosis-specific exercises have demonstrated promising results in reducing the progression of AIS.

Objectives: The aim of this study was to identify, critically appraise and establish the best available evidence for the effectiveness of Schroth exercises in comparison to non-surgical management to reduce the progression of AIS.

Functional characterization of SCN10A variants in several cases of sudden unexplained death.

Background: Multiple genome-wide association studies (GWAS) and targeted gene sequencing have identified common variants in SCN10A in cases of PR and QRS duration abnormalities, atrial fibrillation and Brugada syndrome. The New York City Office of Chief Medical Examiner has now also identified five SCN10A variants of uncertain significance in six separate cases within a cohort of 330 sudden unexplained death events. The gene product of SCN10A is the Nav1.

Functional characterization of ABCC9 variants identified in sudden unexpected natural death.

Background: Genetic variation in ion channel genes ('channelopathies') are often associated with inherited arrhythmias and sudden death. Genetic testing ('molecular autopsies') of channelopathy genes can be used to assist in determining the likely causes of sudden unexpected death. However, different in silico approaches can yield conflicting pathogenicity predictions and assessing their impact on ion channel function can assist in this regard.

Eye on ion channels in immune cells.

Ion channels facilitate the movement of ions across the plasma and organellar membranes. A recent symposium brought together scientists who study ion channels and transporters in immune cells, which highlighted advances in this emerging field and served to chart new avenues for investigating the roles of ion channels in immunity.

Molecular autopsy: using the discovery of a novel de novo pathogenic variant in the KCNH2 gene to inform healthcare of surviving family.

Background: Molecular testing of the deceased (Molecular Autopsy) is an overlooked area in the United States healthcare system and is not covered by medical insurance, leading to ineffective care for surviving families of thousands of sudden unexpected natural deaths each year. We demonstrated the precision management of surviving family members through the discovery of a novel pathogenic variant in a decedent.

Methods: Forensic investigation and molecular autopsy were performed on an 18-year-old female who died suddenly and unexpectedly.

Functional reclassification of variants of uncertain significance in the HCN4 gene identified in sudden unexpected death.

The HCN4 gene encodes a subunit of the hyperpolarization-activated cyclic nucleotide-gated channel, type 4 that is essential for the proper generation of pacemaker potentials in the sinoatrial node. The HCN4 gene is often present in targeted genetic testing panels for various cardiac conduction system disorders and there are several reports of HCN4 variants associated with conduction disorders. Here, we report the in vitro functional characterization of four rare variants of uncertain significance (VUS) in HCN4, identified through testing a cohort of 296 sudden unexpected natural deaths.

Functional significance of channelopathy gene variants in unexplained death.

Determining the cause of unexplained death in all age groups, including infants, is a priority in forensic medicine. The triple risk model proposed for sudden infant death syndrome involves the intersection of three risks: (1) a critical developmental period in homeostatic control (2), exogenous stressors, and (3) a vulnerable infant. Even though sex and age factor into some forms of inherited arrhythmogenic deaths in young individuals and adults, more appropriate a dual-risk disease model for adults involves exogenous stressors and a vulnerable individual.

Functional characterization of TRPM4 variants identified in sudden unexpected natural death.

Background: The TRPM4 gene encodes the subunit of the Ca-activated nonselective cation channel, which is enriched in the specialized cardiac conduction system and Purkinje fibers. To date, several putative disease-causing variants in TRPM4 have been reported to be associated with cardiac arrhythmia and progressive conduction disease. Here, we report the functional effects of previously uncharacterized variants of uncertain significance (VUS) that we have found while performing a "genetic autopsy" in individuals who have suffered sudden unexpected death (SUD) in the New York City area.

A homozygous SCN5A mutation associated with atrial standstill and sudden death.

Background: Atrial standstill is an arrhythmogenic condition characterized by the absence of spontaneous electrical and mechanical atrial activity or in response to stimulation. There are few reported familial cases which have been associated with SCN5A mutations cosegregating with GJA5 or RYR2; however, isolated SCN5A mutations are rare.

Objective: The purpose of this study was to determine the clinical and biophysical consequence of a novel SCN5A mutation identified in a family with progressive atrial standstill and sudden death.

Regulation of K Channel Trafficking in Pancreatic β-Cells by Protein Histidine Phosphorylation.

Protein histidine phosphatase 1 (PHPT-1) is an evolutionarily conserved 14-kDa protein that dephosphorylates phosphohistidine. mice were generated to gain insight into the role of PHPT-1 and histidine phosphorylation/dephosphorylation in mammalian biology. mice exhibited neonatal hyperinsulinemic hypoglycemia due to impaired trafficking of K channels to the plasma membrane in pancreatic β-cells in response to low glucose and leptin and resembled patients with congenital hyperinsulinism (CHI).

Applying High-Resolution Variant Classification to Cardiac Arrhythmogenic Gene Testing in a Demographically Diverse Cohort of Sudden Unexplained Deaths.

Background: Genetic variant interpretation contributes to testing yield differences reported for sudden unexplained death. Adapting a high-resolution variant interpretation framework, which considers disease prevalence, reduced penetrance, genetic heterogeneity, and allelic contribution to determine the maximum tolerated allele count in gnomAD, we report an evaluation of cardiac channelopathy and cardiomyopathy genes in a large, demographically diverse sudden unexplained death cohort that underwent thorough investigation in the United States' largest medical examiner's office.

Methods And Results: The cohort has 296 decedents: 147 Blacks, 64 Hispanics, 49 Whites, 22 Asians, and 14 mixed ethnicities; 142 infants (1 to 11 months), 39 children (1 to 17 years), 74 young adults (18 to 34 years), and 41 adults (35 to 55 years).