Dyssynchronous (non-uniform) Ca2+ release in myocytes from streptozotocin-induced diabetic rats

Chun Hong Shao, George J. Rozanski, Kaushik P. Patel, Keshore R. Bidasee

Research output: Contribution to journalArticle

61 Scopus citations

Abstract

Using biochemical/pharmacological approaches, we previously showed that type 2 ryanodine receptors (RyR2) become dysfunctional in hearts of streptozotocin-induced type 1 diabetic rats. However, the functional consequence of this observation remains incompletely understood. Here we use laser confocal microscopy to investigate whether RyR2 dysfunction during diabetes alters evoked and spontaneous Ca2+ release from the sarcoplasmic reticulum (SR). After 7-8 weeks of diabetes, steady-state levels of RyR2 remain unchanged in hearts of male Sprague-Dawley rats, but the number of functional receptors decreased by > 37%. Interestingly, residual functional RyR2 from diabetic rat hearts exhibited increased sensitivity to Ca2+ activation (EC50activation decreased from 80 μM to 40 μM, peak Ca2+ activation decreased from 425 μM to 160 μM). When field stimulated, intracellular Ca2+ release in diabetic ventricular myocytes was dyssynchronous (non-uniform) and this was independent of L-type Ca2+ currents. Time to peak Ca2+ increased 3.7-fold. Diabetic myocytes also exhibited diastolic Ca2+ release and 2-fold higher frequency of spontaneous Ca2+ sparks, albeit at a lower amplitude. The amplitude of caffeine-releasable Ca2+ was also lower in diabetic myocytes. RyR2 from diabetic rat hearts exhibited increased phosphorylation at Ser2809 and contained reduced levels of FKBP12.6 (calstablin2). Collectively, these data suggest that RyR2 becomes leaky during diabetes and this defect may be responsible to the reduced SR Ca2+ load. Diastolic Ca2+ release could also serve as a substrate for delayed after-depolarizations, contributing to the increased incidence of arrhythmias and sudden cardiac death in type 1 diabetes.

Original languageEnglish (US)
Pages (from-to)234-246
Number of pages13
JournalJournal of Molecular and Cellular Cardiology
Volume42
Issue number1
DOIs
StatePublished - Jan 1 2007

Keywords

  • Ca sparks
  • Ca transients
  • Diabetes
  • Dysregulation
  • Rat
  • Ryanodine receptors

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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