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

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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

Fingerprint

Calcium-Calmodulin-Dependent Protein Kinase Type 2
Knockout Mice
Adrenergic Receptors
Heart Ventricles
Calcium
Workload
Isoproterenol
Adrenergic Agents
Muscle Cells
Excitation Contraction Coupling
Sarcomeres
Echocardiography
Heart Rate
Western Blotting
Proteins

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Xu, L., Lai, D., Cheng, J., Lim, H. J., Keskanokwong, T., Backs, J., ... Wang, Y. (2010). Alterations of L-type calcium current and cardiac function in CaMKII δ knockout mice. Circulation Research, 107(3), 398-407. https://doi.org/10.1161/CIRCRESAHA.110.222562

Alterations of L-type calcium current and cardiac function in CaMKII δ knockout mice. / Xu, Lin; Lai, Dongwu; Cheng, Jun; Lim, Hyun Joung; Keskanokwong, Thitima; Backs, Johannes; Olson, Eric N.; Wang, Yanggan.

In: Circulation Research, Vol. 107, No. 3, 06.08.2010, p. 398-407.

Research output: Contribution to journalArticle

Xu, L, Lai, D, Cheng, J, Lim, HJ, Keskanokwong, T, Backs, J, Olson, EN & Wang, Y 2010, 'Alterations of L-type calcium current and cardiac function in CaMKII δ knockout mice', Circulation Research, vol. 107, no. 3, pp. 398-407. https://doi.org/10.1161/CIRCRESAHA.110.222562
Xu, Lin ; Lai, Dongwu ; Cheng, Jun ; Lim, Hyun Joung ; Keskanokwong, Thitima ; Backs, Johannes ; Olson, Eric N. ; Wang, Yanggan. / Alterations of L-type calcium current and cardiac function in CaMKII δ knockout mice. In: Circulation Research. 2010 ; Vol. 107, No. 3. pp. 398-407.
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