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Physiological modulation of inactivation in L‐type Ca 2+ channels: one switch
Author(s) -
Findlay Ian
Publication year - 2004
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2003.047902
Subject(s) - depolarization , endoplasmic reticulum , stimulation , biophysics , chemistry , endocrinology , biology , biochemistry
The relative contributions of voltage‐ and Ca 2+ ‐dependent mechanisms of inactivation to the decay of L‐type Ca 2+ channel currents ( I CaL ) is an old story to which recent results have given an unexpected twist. In cardiac myocytes voltage‐dependent inactivation (VDI) was thought to be slow and Ca 2+ ‐dependent inactivation (CDI) resulting from Ca 2+ influx and Ca 2+ ‐induced Ca 2+ ‐release (CICR) from the sarcoplasmic reticulum provided an automatic negative feedback mechanism to limit Ca 2+ entry and the contribution of I CaL to the cardiac action potential. Physiological modulation of I CaL by β‐adrenergic and muscarinic agonists then involved essentially more or less of the same by enhancing or reducing Ca 2+ channel activity, Ca 2+ influx, sarcoplasmic reticulum load and thus CDI. Recent results on the other hand place VDI at the centre of the regulation of I CaL . Under basal conditions it has been found that depolarization increases the probability that an ion channel will show rapid VDI. This is prevented by β‐adrenergic stimulation. Evidence also suggests that a channel which shows rapid VDI inactivates before CDI can become effective. Therefore the contributions of VDI and CDI to the decay of I CaL are determined by the turning on, by depolarization, and the turning off, by phosphorylation, of the mechanism of rapid VDI. The physiological implications of these ideas are that under basal conditions the contribution of I CaL to the action potential will be determined largely by voltage and by Ca 2+ following β‐adrenergic stimulation.