Alterations of L-type calcium current and cardiac function in CaMKII δ knockout mice

Lin Xu, Dongwu Lai, Jun Cheng, Hyun Joung Lim, Thitima Keskanokwong, Johannes Backs, Eric N. Olson, Yanggan Wang

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

Rationale: Recent studies have highlighted important roles of CaMKII in regulating Ca2+handling and excitation-contraction coupling. However, the cardiac effect of chronic CaMKII inhibition has not been well understood. Objective: We have tested the alterations of L-type calcium current (I Ca) and cardiac function in CaMKIIδ knockout (KO) mouse left ventricle (LV). Methods and Results: We used the patch-clamp method to record ICain ventricular myocytes and found that in KO LV, basal I Cawas significantly increased without changing the transmural gradient of ICadistribution. Substitution of Ba2+for Ca2+showed similar increase in IBa. There was no change in the voltage dependence of ICaactivation and inactivation. I Carecovery from inactivation, however, was significantly slowed. In KO LV, the Ca2+-dependent ICafacilitation (CDF) and I Caresponse to isoproterenol (ISO) were significantly reduced. However, ISO response was reversed by β2-adrenergic receptor (AR) inhibition. Western blots showed a decrease in β1-AR and an increase in Cav1.2, β2-AR, and Gαi3 protein levels. Ca 2+transient and sarcomere shortening in KO myocytes were unchanged at 1-Hz but reduced at 3-Hz stimulation. Echocardiography in conscious mice revealed an increased basal contractility in KO mice. However, cardiac reserve to work load and β-adrenergic stimulation was reduced. Surprisingly, KO mice showed a reduced heart rate in response to work load or β-adrenergic stimulation. Conclusions: Our results implicate physiological CaMKII activity in maintaining normal ICa, Ca2+handling, excitationcontraction coupling, and the in vivo heart function in response to cardiac stress.

Original languageEnglish (US)
Pages (from-to)398-407
Number of pages10
JournalCirculation research
Volume107
Issue number3
DOIs
StatePublished - Aug 6 2010

Keywords

  • CaMKII
  • Calcium channel
  • Excitation-contraction coupling
  • Myocytes

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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