Hormonal and neurotransmitter regulation of Ca++ influx through voltage-dependent slow channels in cardiac muscle membrane.

The voltage- and time-dependent slow channels in the myocardial cell membrane are the major pathway by which Ca++ ions enter the cell during excitation for initiation and regulation of the force of contraction of cardiac muscle. These slow channels behave kinetically as if their gates open, close, and recover more slowly than those of the fast Na+ channels; in addition, the slow channel gates operate over a less negative (more depolarized) voltage range. Tetrodotoxin does not block the slow channels, whereas the calcium antagonistic drugs, Mn++, Co++, and La ions do. The slow channels have some special properties, including their functional dependence on metabolic energy, their selective blockade by acidosis, and their regulation by cyclic AMP level. Because of their regulation by cyclic AMP, it is proposed that either the slow channel protein or an associated regulatory protein must be phosphorylated in order for the channel to be made available for voltage activation during excitation. That is, the dephosphorylated channel would be electrically silent. The requirement for phosphorylation allows the extrinsic control of the slow channels and Ca++ influx by neurotransmitters, hormones, and autacoids that affect the cyclic nucleotide levels.