Regulation of Cardiac L-Type Calcium Channels by Protein Kinase A and Protein Kinase C

Abstract

Abstract —Voltage-dependent L-type Ca 2+ channels are multisubunit transmembrane proteins, which allow the influx of Ca 2+ ( I Ca ) essential for normal excitability and excitation-contraction coupling in cardiac myocytes. A variety of different receptors and signaling pathways provide dynamic regulation of I Ca in the intact heart. The present review focuses on recent evidence describing the molecular details of regulation of L-type Ca 2+ channels by protein kinase A (PKA) and protein kinase C (PKC) pathways. Multiple G protein–coupled receptors act through cAMP/PKA pathways to regulate L-type channels. β-Adrenergic receptor stimulation results in a marked increase in I Ca , which is mediated by a cAMP/PKA pathway. Growing evidence points to an important role of localized signaling complexes involved in the PKA-mediated regulation of I Ca , including A-kinase anchor proteins and binding of phosphatase PP2a to the carboxyl terminus of the α 1C (Ca v 1.2) subunit. Both α 1C and β 2a subunits of the channel are substrates for PKA in vivo. The regulation of L-type Ca 2+ channels by Gq-linked receptors and associated PKC activation is complex, with both stimulation and inhibition of I Ca being observed. The amino terminus of the α 1C subunit is critically involved in PKC regulation. Crosstalk between PKA and PKC pathways occurs in the modulation of I Ca . Ultimately, precise regulation of I Ca is needed for normal cardiac function, and alterations in these regulatory pathways may prove important in heart disease.