BIN1 knockdown rescues systolic dysfunction in aging male mouse hearts.

Cardiac dysfunction is a hallmark of aging in humans and mice. Here we report that a two-week treatment to restore youthful Bridging Integrator 1 (BIN1) levels in the hearts of 24-month-old mice rejuvenates cardiac function and substantially reverses the aging phenotype. Our data indicate that age-associated overexpression of BIN1 occurs alongside dysregulated endosomal recycling and disrupted trafficking of cardiac Ca1.

Acute phosphatidylinositol 4,5 bisphosphate depletion destabilizes sarcolemmal expression of cardiac L-type Ca channel Ca1.2.

Ca1.2 channels are critical players in cardiac excitation-contraction coupling, yet we do not understand how they are affected by an important therapeutic target of heart failure drugs and regulator of blood pressure, angiotensin II. Signaling through G-coupled AT1 receptors, angiotensin II triggers a decrease in PIP, a phosphoinositide component of the plasma membrane (PM) and known regulator of many ion channels.

Molecular Pathology of Sodium Channel Beta-Subunit Variants.

The voltage-gated Na channel regulates the initiation and propagation of the action potential in excitable cells. The major cardiac isoform Na1.5, encoded by , comprises a monomer with four homologous repeats (I-IV) that each contain a voltage sensing domain (VSD) and pore domain.

The Therapeutic Landscape of Rheumatoid Arthritis: Current State and Future Directions.

Rheumatoid arthritis (RA) is a debilitating autoimmune disease with grave physical, emotional and socioeconomic consequences. Despite advances in targeted biologic and pharmacologic interventions that have recently come to market, many patients with RA continue to have inadequate response to therapies, or intolerable side effects, with resultant progression of their disease. In this review, we detail multiple biomolecular pathways involved in RA disease pathogenesis to elucidate and highlight pathways that have been therapeutic targets in managing this systemic autoimmune disease.

β-Adrenergic control of sarcolemmal Ca1.2 abundance by small GTPase Rab proteins.

The number and activity of Ca1.2 channels in the cardiomyocyte sarcolemma tunes the magnitude of Ca-induced Ca release and myocardial contraction. β-Adrenergic receptor () activation stimulates sarcolemmal insertion of Ca1.

Predicting Patient Response to the Antiarrhythmic Mexiletine Based on Genetic Variation.

Rationale: Mutations in the SCN5A gene, encoding the α subunit of the Nav1.5 channel, cause a life-threatening form of cardiac arrhythmia, long QT syndrome type 3 (LQT3). Mexiletine, which is structurally related to the Na channel-blocking anesthetic lidocaine, is used to treat LQT3 patients.

Mechanisms and models of cardiac sodium channel inactivation.

Shortly after cardiac Na channels activate and initiate the action potential, inactivation ensues within milliseconds, attenuating the peak Na current, I and allowing the cell membrane to repolarize. A very limited number of Na channels that do not inactivate carry a persistent I, or late I. While late I is only a small fraction of peak magnitude, it significantly prolongs ventricular action potential duration, which predisposes patients to arrhythmia.

Mechanisms of noncovalent β subunit regulation of Na channel gating.

Voltage-gated Na (Na) channels comprise a macromolecular complex whose components tailor channel function. Key components are the non-covalently bound β1 and β3 subunits that regulate channel gating, expression, and pharmacology. Here, we probe the molecular basis of this regulation by applying voltage clamp fluorometry to measure how the β subunits affect the conformational dynamics of the cardiac Na channel (Na1.

Regulation of Na channel inactivation by the DIII and DIV voltage-sensing domains.

Functional eukaryotic voltage-gated Na (Na) channels comprise four domains (DI-DIV), each containing six membrane-spanning segments (S1-S6). Voltage sensing is accomplished by the first four membrane-spanning segments (S1-S4), which together form a voltage-sensing domain (VSD). A critical Na channel gating process, inactivation, has previously been linked to activation of the VSDs in DIII and DIV.