Regulation of L-type calcium channels of vascular smooth muscle cells.

Vascular tone is regulated by a variety of neurotransmitters, vasoactive hormones and autacoids, and vasoactive drugs. These actions are mediated, at least in part, by actions on the membrane ion channels, exerted either directly or indirectly. In this article, we described evidence that four different protein kinase systems (PK-A, PK-G, PK-C, and Ca2+/CaM-PK) act on and modulate the L-type Ca2+ slow channels in VSM cells and other types of cells. In cardiac muscle, both cAMP/PK-A and cGMP/PK-G have opposing effects. cAMP/PK-A stimulating and cGMP/PK-G inhibiting. In VSM, both cyclic nucleotides and their related kinases act in the same direction, namely both inhibit ICa(L). In skeletal muscle, both cAMP and cGMP also act in the same direction on ICa(L), but to stimulate. Ca2+ channel phosphorylation may be an important mechanism for the cyclic nucleotide-dependent actions of some vasodilators. In cardiac muscle, in addition to the slower indirect pathway--exerted via cAMP/PK-A--there is a faster more-direct pathway for ICa(L) stimulation by the beta-adrenergic receptor. This latter pathway involves direct modulation of the channel activity by the alpha subunit of the Gs-protein (Gs alpha). The two pathways (direct and indirect) are also present in VSM cells, although the indirect pathway produces inhibition of ICa(L)). PK-C and calmodulin-PK also may play roles in regulation of the L-type Ca2+ channels in smooth muscle cells, possibly mediated by phosphorylation of some regulatory-type of protein. Thus, it appears that the L-type Ca2+ slow channel is a complex structure, including perhaps several associated regulatory proteins, which can be regulated by a number of factors intrinsic and extrinsic to the cell (Figs 9, 14).