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The adhesion function of the sodium channel beta subunit (β1) contributes to cardiac action potential propagation.

ABSTRACT: Computational modeling indicates that cardiac conduction may involve ephaptic coupling - intercellular communication involving electrochemical signaling across narrow extracellular clefts between cardiomyocytes. We hypothesized that β1(SCN1B) -mediated adhesion scaffolds trans-activating NaV1.5 (SCN5A) channels within narrow (<30 nm) perinexal clefts adjacent to gap junctions (GJs), facilitating ephaptic coupling. Super-resolution imaging indicated preferential β1 localization at the perinexus, where it co-locates with NaV1.5. Smart patch clamp (SPC) indicated greater sodium current density (INa) at perinexi, relative to non-junctional sites. A novel, rationally designed peptide, βadp1, potently and selectively inhibited β1-mediated adhesion, in electric cell-substrate impedance sensing studies. βadp1 significantly widened perinexi in guinea pig ventricles, and selectively reduced perinexal INa, but not whole cell INa, in myocyte monolayers. In optical mapping studies, βadp1 precipitated arrhythmogenic conduction slowing. In summary, β1-mediated adhesion at the perinexus facilitates action potential propagation between cardiomyocytes, and may represent a novel target for anti-arrhythmic therapies.

SUBMITTER: Veeraraghavan R

PROVIDER: S-EPMC6122953 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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The adhesion function of the sodium channel beta subunit (β1) contributes to cardiac action potential propagation.

Veeraraghavan Rengasayee R Hoeker Gregory S GS Alvarez-Laviada Anita A Hoagland Daniel D Wan Xiaoping X King D Ryan DR Sanchez-Alonso Jose J Chen Chunling C Jourdan Jane J Isom Lori L LL Deschenes Isabelle I Smyth James W JW Gorelik Julia J Poelzing Steven S Gourdie Robert G RG

eLife 20180814

Computational modeling indicates that cardiac conduction may involve ephaptic coupling - intercellular communication involving electrochemical signaling across narrow extracellular clefts between cardiomyocytes. We hypothesized that β1(SCN1B) -mediated adhesion scaffolds <i>trans</i>-activating Na<sub>V</sub>1.5 (SCN5A) channels within narrow (<30 nm) perinexal clefts adjacent to gap junctions (GJs), facilitating ephaptic coupling. Super-resolution imaging indicated preferential β1 localization ...[more]

PMID: 30106376

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Project description:Key pointsAssociation of plasma membrane BKCa channels with BK-β subunits shapes their biophysical properties and physiological roles; however, functional modulation of the mitochondrial BKCa channel (mitoBKCa ) by BK-β subunits is not established. MitoBKCa -α and the regulatory BK-β1 subunit associate in mouse cardiac mitochondria. A large fraction of mitoBKCa display properties similar to that of plasma membrane BKCa when associated with BK-β1 (left-shifted voltage dependence of activation, V1/2 = -55 mV, 12 µm matrix Ca2+ ). In BK-β1 knockout mice, cardiac mitoBKCa displayed a low Po and a depolarized V1/2 of activation (+47 mV at 12 µm matrix Ca2+ ) Co-expression of BKCa with the BK-β1 subunit in HeLa cells doubled the density of BKCa in mitochondria. The present study supports the view that the cardiac mitoBKCa channel is functionally modulated by the BK-β1 subunit; proper targeting and activation of mitoBKCa shapes mitochondrial Ca2+ handling.AbstractAssociation of the plasma membrane BKCa channel with auxiliary BK-β1-4 subunits profoundly affects the regulatory mechanisms and physiological processes in which this channel participates. However, functional association of mitochondrial BK (mitoBKCa ) with regulatory subunits is unknown. We report that mitoBKCa functionally associates with its regulatory subunit BK-β1 in adult rodent cardiomyocytes. Cardiac mitoBKCa is a calcium- and voltage-activated channel that is sensitive to paxilline with a large conductance for K+ of 300 pS. Additionally, mitoBKCa displays a high open probability (Po ) and voltage half-activation (V1/2 = -55 mV, n = 7) resembling that of plasma membrane BKCa when associated with its regulatory BK-β1 subunit. Immunochemistry assays demonstrated an interaction between mitochondrial BKCa -α and its BK-β1 subunit. Mitochondria from the BK-β1 knockout (KO) mice showed sparse mitoBKCa currents (five patches with mitoBKCa activity out of 28 total patches from n = 5 different hearts), displaying a depolarized V1/2 of activation (+47 mV in 12 µm matrix Ca2+ ). The reduced activity of mitoBKCa was accompanied by a high expression of BKCa transcript in the BK-β1 KO, suggesting a lower abundance of mitoBKCa channels in this genotype. Accordingly, BK-β1subunit increased the localization of BKDEC (i.e. the splice variant of BKCa that specifically targets mitochondria) into mitochondria by two-fold. Importantly, both paxilline-treated and BK-β1 KO mitochondria displayed a more rapid Ca2+ overload, featuring an early opening of the mitochondrial transition pore. We provide strong evidence that mitoBKCa associates with its regulatory BK-β1 subunit in cardiac mitochondria, ensuring proper targeting and activation of the mitoBKCa channel that helps to maintain mitochondrial Ca2+ homeostasis.

Dataset Information

The adhesion function of the sodium channel beta subunit (β1) contributes to cardiac action potential propagation.

Publications

The adhesion function of the sodium channel beta subunit (β1) contributes to cardiac action potential propagation.

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