The voltage-dependent slow channels in the myocardial cell membrane are the major pathway by which Ca
2+ ions enter the cell during excitation for initiation and regulation of the force of contraction of cardiac muscle. The slow channels have some special properties, including functional dependence on metabolic energy, selective blockade by acidosis, and regulation by the intracellular cyclic nucleotide levels. Because of these special properties of the slow channels, Ca
2+ influx into the myocardial cell can be controlled by extrinsic factors (such as autonomic nerve stimulation or circulating hormones) and by intrinsic factors (such as cellular pH or ATP level). The slow Ca
2+ channels of the heart are regulated by cAMP in a stimulatory fashion. Elevation of cAMP produces a very rapid increase in number of slow channels available for voltage activation during excitation. The probability of a slow 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
si, Ca
2+ influx, and contraction. The myocardial slow Ca
2+ channels are also regulated by cGMP, in a manner that is opposite to that of CAMP. The effect of cGMP is presumably mediated by means of phosphorylation of a protein, as for example, a regulatory protein (inhibitory-type) associated with the slow channel. Preliminary data suggest that calmodulin also may play a role in regulation of the myocardial slow Ca
2+ channels, possibly mediated by the Ca
2+-calmodulin-protein kinase and phosphorylation of some regulatory-type of protein. Thus, it appears that the slow Ca
2+ channel is a complex structure, including perhaps several associated regulatory proteins, which can be regulated by a number of extrinsic and intrinsic factors.VSM cells contain two types of Ca
2+ channels: slow (L-type) Ca
2+ channels and fast (T-type) Ca
2+ channels. Although regulation of voltage-dependent Ca
2+ slow channels of VSM cells have not been fully clarified yet, we have made some progress towards answering this question. Slow (L-type, high-threshold) Ca
2+ channels may be modified by phosphorylation of the channel protein or an associated regulatory protein. In contrast to cardiac muscle where cAMP and cGMP have antagonistic effects on Ca
2+ slow channel activity, in VSM, cAMP and cGMP have similar effects, namely inhibition of the Ca
2+ slow channels. Thus, any agent that elevates cAMP or cGMP will inhibit Ca
2+ influx, and thereby act to produce vasodilation. The Ca
2+ slow channels require ATP for activity, with a K
0.5 of about 0.3 mM. C-kinase may stimulate the Ca
2+ slow channels by phosphorylation. G-protein may have a direct action on the Ca
2+ channels, and may mediate the effects of activation of some receptors. These mechanisms of Ca
2+ channel regulation may be invoked during exposure to agonists or drugs, which change second messenger levels, thereby controlling vascular tone.
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