Δευτέρα 4 Φεβρουαρίου 2019

β‐adrenergic‐mediated dynamic augmentation of sarcolemmal CaV1.2 clustering and cooperativity in ventricular myocytes

Abstract

Voltage‐dependent L‐type CaV1.2 channels play an indispensable role in cardiac excitation‐contraction (EC) coupling. Activation of the β‐adrenergic receptor (βAR)/cAMP/PKA signaling pathway leads to enhanced CaV1.2 activity resulting in increased Ca2+ influx into ventricular myocytes, and a positive inotropic response. CaV1.2 channels exhibit a clustered distribution along the T‐tubule sarcolemma of ventricular myocytes where nanometer proximity between channels permits Ca2+‐dependent cooperative gating behaviour mediated by dynamic, physical, allosteric interactions between adjacent channel C‐terminal tails. This amplifies Ca2+ influx and augments myocyte Ca2+ transient and contraction amplitudes. We investigated whether βAR signaling could alter CaV1.2 channel clustering to facilitate cooperative channel interactions and elevate Ca2+ influx in ventricular myocytes. Bimolecular fluorescence complementation experiments reveal that the βAR agonist, isoproterenol (ISO), promotes enhanced CaV1.2‐CaV1.2 physical interactions. Super‐resolution nanoscopy and dynamic channel tracking indicate that these interactions are expedited by enhanced spatial proximity between channels, resulting in the appearance of CaV1.2 'super‐clusters' along the z‐lines of ISO‐stimulated cardiomyocytes. The mechanism that leads to super‐cluster formation involves rapid, dynamic augmentation of sarcolemmal CaV1.2 channel abundance after ISO application. Optical and electrophysiological single channel recordings confirm that these newly inserted channels are functional and contribute to overt cooperative gating behaviour of CaV1.2 channels in ISO stimulated myocytes. Our study reveals a new facet of βAR‐mediated regulation of CaV1.2 channels in the heart and supports the novel concept that a pre‐synthesized pool of sub‐sarcolemmal CaV1.2 channel‐containing vesicles/endosomes reside in cardiomyocytes and can be mobilized to the sarcolemma to tune EC‐coupling to meet metabolic and/or hemodynamic demands.

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