title: Regulation of slow calcium channels of myocardial cells and vascular smooth muscle cells by cyclic nucleotides and phosphorylation.
abstract: 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 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 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 ICa(L) in both chick and rat heart cells. Such inhibition occurs for both the basal and stimulated ICa(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 ICa(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 Gs-protein. In vascular smooth muscle cells the two pathways (direct and indirect) also appear to be present, although the indirect pathway produces inhibition of ICa(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, and thereby control can be exercised over the force of contraction of the heart.
authors.affiliation: Department of Physiology and Biophysics, University of Cincinnati, OH 45267-0576.
authors.forename: N
authors.initials: N
authors.lastname: Sperelakis
authors.forename: Z
authors.initials: Z
authors.lastname: Xiong
authors.forename: G
authors.initials: G
authors.lastname: Haddad
authors.forename: H
authors.initials: H
authors.lastname: Masuda
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D006321:Heart / Q000502:physiology*; D006706:Homeostasis; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D010766:Phosphorylation
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D015124:8-Bromo Cyclic Adenosine Monophosphate; C016276:8-bromocyclic GMP; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D006152:Cyclic GMP; D002118:Calcium