Dual regulation of Ca2+/calmodulin-dependent kinase II activity by membrane voltage and by calcium influx

Rui Ping Xiao, Heping Cheng, W. J. Lederer, Tatsuo Suzuki, Edward G. Lakatta

Research output: Contribution to journalArticlepeer-review

171 Scopus citations


Calcium entry through voltage-gated Ca2+ channels is critical in cardiac excitation-contraction coupling and calcium metabolism. In this report, we demonstrate both spatially resolved and temporally distinct effects of Ca2+/ calmodulin-dependent protein kinase II (CaMKII) on L-type Ca2+ channel current (ICa) in rat cardiac myocytes. Either depolarization alone or calcium influx can increase the amplitude and slow the inactivation of ICa. The distinct voltage- and Ca2+-dependent effects persist with time constants of ≈1.7 sec and 9 sec, respectively. Both effects are completely abolished by a specific peptide inhibitor of CaMKII. This CaMKII inhibitor also suppresses the prolongation of ICa induced by depolarizing holding potentials. Furthermore, using an antibody specific for the autophosphorylated (activated) CaMKII, we find that this kinase is localized close to sarcolemmal membranes and that the profile of CaMKII activation correlates qualitatively with the changes in ICa under various conditions. Therefore, we conclude that the action of CaMKII on ICa is dually regulated by membrane depolarization and by Ca2+ influx; the latter directly activates CaMKII, whereas the former likely promotes the interaction between constitutive CaMKII and the membrane-channel proteins. These regulatory mechanisms provide positive-feedback control of Ca2+ channels and are probably important in the regulation of cardiac contractility and other intracellular Ca2+-regulated processes.

Original languageEnglish (US)
Pages (from-to)9659-9663
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number20
StatePublished - Sep 27 1994
Externally publishedYes


  • Autophosphorylation
  • Calcium channel facilitation
  • Confocal microscopy
  • Heart cells

ASJC Scopus subject areas

  • General


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