REGULATION OF SLOW CALCIUM CHANNELS OF MYOCARDIAL-CELLS AND VASCULAR SMOOTH-MUSCLE CELLS BY CYCLIC-NUCLEOTIDES AND PHOSPHORYLATION

The slow Ca2(+) channels (L-type) of the heart are stimulated by cAMP. Elevation of cAMP produces a very rapid increase in number of slow channels available for voltage activation during excitation. The probability of a Ca2(+) channel opening and the mean open time of the channel are increased. Therefore, any agent that increases the cAMP level of the myocardial cell will tend to potentiate I-Ca, Ca2(+) influx, and contraction. The action of cAMP is mediated by PK-A and phosphorylation of the slow Ca2(+) channel protein or an associated regulatory protein (stimulatory type). The myocardial slow Ca2(+) channels are also regulated by cGMP, in a manner that is opposite or antagonistic to that of cAMP. We have demonstrated this at both the macroscopic level (whole-cell voltage clamp) and the single-channel level. The effect of cGMP is mediated by PK-G and phosphorylation of a protein, as for example, a regulatory protein (inhibitory-type) associated with the Ca2(+) channel. Introduction of PK-G intracellularly causes a relatively rapid inhibition of I-Ca(L) in both chick and rat heart cells. Such inhibition occurs for both the basal and stimulated I-Ca(L). In addition, the cGMP/PK-G system was reported to stimulate a phosphatase that dephosphorylates the Ca2+ channel. In addition to the slower indirect pathway - exerted via cAMP/PK-A - there is a faster more-direct pathway for I-Ca(L) stimulation by the beta-adrenergic receptor. This latter pathway involves direct modulation of the channel activity by the alpha subunit (alpha(s)*) of the G(s)-protein. In vascular smooth muscle cells the two pathways (direct and indirect) also appear to be present, although the indirect pathway produces inhibition of I-Ca(L). PK-C and calmodulin-PK also may play roles in regulation of the myocardial slow Ca2+ channels, Both of these protein kinases stimulate the activity of these channels. Thus, it appears that the slow Ca2+ 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, acid thereby control can be exercised over the force of contraction of the heart.