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Regulation of slow calcium channels of myocardial cells and vascular smooth muscle cells by cyclic nucleotides and phosphorylation

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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 rogulated by cGMP, in a manner that is opposite orantagonistic to that of cAMP. We have demonstrated this at both the macroscople 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 β-adrenergic receptor. This latter pathway involves direct modulation of the channel activity by the alpha subunit (αs*) of the Gs-protein. In vascular smooth muscle cells the two pathways (direct and indirect) also appear to be present, although the indirect pathway producesinhibition 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.

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Authors and Affiliations

  1. Department of Physiology and Biophysics, University of Cincinnati, 45267-0576, Cincinnati, OH, USA

    Nicholas Sperelakis, Zhiling Xiong, G. Haddad & Hiroshi Masuda

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  1. Nicholas Sperelakis
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  2. Zhiling Xiong
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  3. G. Haddad
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  4. Hiroshi Masuda
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This review-type article was prepared by modifying an article published in a book by Sperelakiset al., 1994.

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Sperelakis, N., Xiong, Z., Haddad, G. et al. Regulation of slow calcium channels of myocardial cells and vascular smooth muscle cells by cyclic nucleotides and phosphorylation. Mol Cell Biochem 140, 103–117 (1994). https://doi.org/10.1007/BF00926749

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