Regulation of calcium slow channels of heart by cyclic nucleotides and effects of ischemia.

The slow Ca2+ channels (L-type) of the heart are stimulated by cAMP. Elevation of cAMP produces a very rapid increase in the 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 ICa, 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 of that of cAMP. This has been demonstrated 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, for example, a regulatory protein (inhibitory type) associated with the Ca2+ channel. It has been demonstrated that introduction of PK-G intracellularly causes a relatively rapid inhibition of ICa(L) in both chick and rat heart cells. In addition, cGMP/PK-G act 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 ICa(L) stimulation by the beta-adrenergic receptor. The latter pathway involves direct modulation of the channel activity by the alpha subunit (alpha S*) of the GS protein. PK-C and calmodulin-PK also may play roles in the regulation of the myocardial slow Ca2+ channels, possibly mediated by phosphorylation of some regulatory type of protein. Both protein kinases stimulate the activity of the slow Ca2+ 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 (Fig. 9). The cyclic nucleotides also have effects on the slow Ca2+ channels in cells other than cardiac muscle, including neurons, smooth muscle, and skeletal muscle fibers (Tables III and IV). In cardiac muscle, the two cyclic nucleotides have opposing effects, cAMP stimulating and cGMP inhibiting. In some smooth muscles (e.g., vascular), both cyclic nucleotides act in the same direction, namely, both inhibit ICa(L). In skeletal muscle, both cAMP and cGMP act in the same direction on ICa(L), but to stimulate.(ABSTRACT TRUNCATED AT 400 WORDS)