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

Abstract

Abstract-Voltage-dependent L-type Ca 2ϩ channels are multisubunit transmembrane proteins, which allow the influx of Ca 2ϩ (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 2ϩ 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. ␤-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 ␣ 1C (Ca v 1.2) subunit. Both ␣ 1C and ␤ 2a subunits of the channel are substrates for PKA in vivo. The regulation of L-type Ca 2ϩ 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 ␣ 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. (Circ Res. 2000;87:1095-1102.)Key Words: L-type calcium channel Ⅲ protein kinase C Ⅲ protein kinase A Ⅲ heart Ⅲ regulation Ⅲ phosphorylation T he influx of Ca 2ϩ ions through voltage-dependent L-type Ca 2ϩ channels plays an essential role in cardiac excitability and in coupling excitation to contraction. The depolarizing current through L-type Ca 2ϩ channels (I Ca ) contributes to the plateau phase of the cardiac action potential as well as to pacemaker activity in nodal cells. This influx of Ca 2ϩ triggers the release of intracellular stores of Ca 2ϩ from the sarcoplasmic reticulum, and the ensuing intracellular Ca 2ϩ transient results in activation of the myofilaments. L-type channels can also impact on other cellular processes modulated by intracellular Ca 2ϩ such as gene expression and excitation-secretion coupling. Alterations in density or function of L-type Ca 2ϩ channels have been implicated in a variety of cardiovascular diseases, including atrial fibrillation, 1,2 heart failure, 3-6 and ischemic heart disease. 7 Cardiac L-type Ca 2ϩ channels are regulated by a variety of neurotransmitters, hormones, and cytokines. In fact, the first description of currents carried by this channel revealed its regulation by epinephrine. 8 Sperelakis and Schneider 9 and Reuter and Scholz 10 independently hypothesized that ␤-adrenergic receptor (AR)-mediated stimulation of cardiac L-type Ca 2ϩ channels was due to phosphorylation of the channel by cAMP-dependent protein kinase A (PKA). Extensive electrophysiology experi...

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