Regulation of cardiac L-type calcium channels by protein kinase A and protein kinase C

Voltage-dependent L-type Ca2+ channels Lire multisubunit transmembrane prot eins, which allow the influx of Ca2+ (I-Ca) essential for normal excitabili ty and excitation-contraction coupling in cardiac myocytes. A variety of di fferent receptors and signaling pathways provide dynamic regulation of I-Ca in the intact heart. The present review focuses on recent evidence describ ing the molecular details of regulation of L-type Ca2+ channels by protein kinase A (PKA) and protein kinase C (PKC) pathways, Multiple G protein-coup led receptors act through cAMP/PKA pathways to regulate L-typr channels. be ta -Adrenerlic receptor stimulation results in a marked increase in I-Ca, w hich is mediated by a cAMP/PKA pathway. Growing evidence points to an impor tant role of localized signaling complexes involved in the PKA-mediated reg ulation of I-Ca, including A-kinase anchor proteins and binding of phosphat ase PP2a to the carboxyl terminus of the alpha (1C) (Ca(v)1.2) Subunit. Bot h alpha (1C) and beta (2a) subunits of the channel are substrates for PKA i n vivo. The regulation of L-type Ca2+ channels by Gq-linked receptors and a ssociated PKC activation is complex, with both stimulation and inhibition o f I-Ca being observed. The amino terminus of the alpha (1C) subunit is crit ically involved in PKC regulation. Crosstalk between PKA and PKC pathways o ccurs in the modulation of I-Ca. Ultimately, precise regulation of I-Ca is needed for normal cardiac function, and alterations in these regulatory pat hways may prove important in heart disease.