Ca2+ and voltage inactivate Ca2+ channels in guinea‐pig ventricular myocytes through independent mechanisms.

R. W. Hadley, W. J. Lederer

Research output: Contribution to journalArticlepeer-review

124 Scopus citations


1. L‐type Ca2+ currents and Ca2+ channel gating currents were studied in isolated guinea‐pig ventricular heart cells using the whole‐cell patch‐clamp technique, in order to investigate the mechanism of Ca(2+)‐dependent inactivation. The effect of altering the intracellular Ca2+ concentration ([Ca2+]i) on these currents was studied through photorelease of intracellular Ca2+ ions using the photolabile Ca2+ chelators DM‐nitrophen and nitr‐5. 2. We found that step increases in [Ca2+]i produced by photorelease could either increase or decrease the L‐type Ca2+ current. Specifically, Ca2+ photorelease from DM‐nitrophen almost exclusively caused inactivation of the Ca2+ current. In contrast, Ca2+ photorelease from nitr‐5 had a biphasic effect: a small, rapid inactivation of the Ca2+ current was followed by a slow potentiation. These two Ca(2+)‐dependent processes seemed to differ in their Ca2+ dependence, as small Ca2+ photoreleases elicited potentiation without a preceding inactivation, whereas larger photoreleases elicited both inactivation and potentiation. 3. The mechanism of the Ca(2+)‐dependent inactivation of Ca2+ channels was explored by comparing the effects of voltage and photoreleased Ca2+ on the Ca2+ current and the Ca2+ channel gating current. Voltage was found to reduce both the Ca2+ current and the gating current proportionally. However, Ca2+ photorelease from intracellular DM‐nitrophen inactivated the Ca2+ current without having any effect on the gating current. 4. The dephosphorylation hypothesis for Ca(2+)‐dependent inactivation was tested by applying isoprenaline to the cells before eliciting a maximal rise of [Ca2+]i (maximal flash intensity, zero external [Na+]i). Isoprenaline could completely prevent Ca(2+)‐dependent inactivation under these conditions, even when [Ca2+]i rose so high as to cause an irreversible contracture of the cell. 5. We concluded from these experiments that voltage and Ca2+ ions inactivate the L‐type Ca2+ channel through separate, independent mechanisms. In addition, we found that Ca(2+)‐dependent inactivation does not result in the immobilization of gating charge, and apparently closes the Ca2+ permeation pathway through a mechanism that does not involve the voltage‐sensing region of the channel. Furthermore, we found that Ca(2+)‐dependent inactivation is entirely sensitive to beta‐adrenergic stimulation. These facts suggest that either Ca(2+)‐dependent inactivation results from Ca(2+)‐dependent dephosphorylation of the Ca2+ channel, or that Ca(2+)‐dependent inactivation is modulated by protein kinase A.

Original languageEnglish
Pages (from-to)257-268
Number of pages12
JournalJournal of Physiology
Issue number1
StatePublished - Dec 1 1991

ASJC Scopus subject areas

  • Physiology


Dive into the research topics of 'Ca2+ and voltage inactivate Ca2+ channels in guinea‐pig ventricular myocytes through independent mechanisms.'. Together they form a unique fingerprint.

Cite this