CaMKII inhibition targeted to the sarcoplasmic reticulum inhibits frequency-dependent acceleration of relaxation and Ca2+ current facilitation

Eckard Picht, Jaime DeSantiago, Sabine Huke, Marcia A. Kaetzel, John R. Dedman, Donald M Bers

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

Abstract

Cardiac Ca2+/calmodulin-dependent protein kinase II (CaMKII) in heart has been implicated in Ca2+ current (ICa) facilitation, enhanced sarcoplasmic reticulum (SR) Ca2+ release and frequency-dependent acceleration of relaxation (FDAR) via enhanced SR Ca2+ uptake. However, questions remain about how CaMKII may work in these three processes. Here we tested the role of CaMKII in these processes using transgenic mice (SR-AIP) that express four concatenated repeats of the CaMKII inhibitory peptide AIP selectively in the SR membrane. Wild type mice (WT) and mice expressing AIP exclusively in the nucleus (NLS-AIP) served as controls. Increasing stimulation frequency produced typical FDAR in WT and NLS-AIP, but FDAR was markedly inhibited in SR-AIP. Quantitative analysis of cytosolic Ca2+ removal during [Ca2+]i decline revealed that FDAR is due to an increased apparent Vmax of SERCA. CaMKII-dependent RyR phosphorylation at Ser2815 and SR Ca2+ leak was both decreased in SR-AIP vs. WT. This decrease in SR Ca2+ leak may partly balance the reduced SERCA activity leading to relatively unaltered SR-Ca2+ load in SR-AIP vs. WT myocytes. Surprisingly, CaMKII regulation of the L-type Ca2+ channel (ICa facilitation and recovery from inactivation) was abolished by the SR-targeted CaMKII inhibition in SR-AIP mice. Inhibition of CaMKII effects on ICa and RyR function by the SR-localized AIP places physical constraints on the localization of these proteins at the junctional microdomain. Thus SR-targeted CaMKII inhibition can directly inhibit the activation of SR Ca2+ uptake, SR Ca2+ release and ICa by CaMKII, effects which have all been implicated in triggered arrhythmias.

Original languageEnglish (US)
Pages (from-to)196-205
Number of pages10
JournalJournal of Molecular and Cellular Cardiology
Volume42
Issue number1
DOIs
StatePublished - Jan 2007
Externally publishedYes

Keywords

  • Calcium
  • CaMKII
  • L-type Ca channel
  • Relaxation
  • Sarcoplasmic reticulum

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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