Ca2+/calmodulin kinase II-dependent phosphorylation of ryanodine receptors suppresses Ca2+ sparks and Ca2+ waves in cardiac myocytes

Dongmei Yang, Wei Zhong Zhu, Bailong Xiao, Didier X.P. Brochet, S. R.Wayne Chen, Edward G. Lakatta, Rui Ping Xiao, Heping Cheng

Research output: Contribution to journalArticlepeer-review

Abstract

The multifunctional Ca/calmodulin-dependent protein kinase II δC (CaMKIIδC) is found in the macromolecular complex of type 2 ryanodine receptor (RyR2) Ca release channels in the heart. However, the functional role of CaMKII-dependent phosphorylation of RyR2 is highly controversial. To address this issue, we expressed wild-type, constitutively active, or dominant-negative CaMKIIδC via adenoviral gene transfer in cultured adult rat ventricular myocytes. CaMKII-mediated phosphorylation of RyR2 was reduced, enhanced, or unaltered by dominant-negative, constitutively active, or wild-type CaMKIIδC expression, whereas phosphorylation of phospholamban at Thr17, an endogenous indicator of CaMKII activity, was at 73%, 161%, or 115% of the control group expressing β-galactosidase (β-gal), respectively. In parallel with the phospholamban phosphorylation, the decay kinetics of global Ca transients was slowed, accelerated, or unchanged, whereas spontaneous Ca spark activity was hyperactive, depressed, or unchanged in dominant-negative, constitutively active, or wild-type CaMKIIδC groups, respectively. When challenged by high extracellular Ca, both wild-type and constitutively active CaMKIIδC protected the cells from store overload-induced Ca release, manifested by a ≈60% suppression of Ca waves (at 2 to 20 mmol/L extracellular Ca) in spite of an elevated sarcoplasmic reticulum Ca content, whereas dominant-negative CaMKIIδC promoted Ca wave production (at 20 mmol/L Ca) with significantly depleted sarcoplasmic reticulum Ca. Taken together, our data support the notion that CaMKIIδC negatively regulates RyR2 activity and spontaneous sarcoplasmic reticulum Ca release, thereby affording a negative feedback that stabilizes local and global Ca-induced Ca release in the heart.

Original languageEnglish (US)
Pages (from-to)399-407
Number of pages9
JournalCirculation research
Volume100
Issue number3
DOIs
StatePublished - Feb 2007

Keywords

  • Ca sparks
  • Ca waves
  • Ca-induced Ca release
  • Ca/calmodulin-dependent protein kinase II
  • Ryanodine receptor

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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