Gain of function of cardiac ryanodine receptor in a rat model of type 1 diabetes

Chengju Tian, Chun Hong Shao, Caronda J. Moore, Shelby Kutty, Timothy Walseth, Cyrus Desouza, Keshore R. Bidasee

Research output: Contribution to journalArticle

Abstract

AimsVentricular myocytes isolated from hearts of streptozotocin (STZ)-diabetic rats exhibit increased spontaneous Ca2+ release. Studies attribute this defect to an enhancement in activity of type 2 ryanodine receptor (RyR2). To date, underlying reasons for RyR2 dysregulation remain undefined. This study assesses whether the responsiveness of RyR2 following stimulation by intrinsic ligands is being altered during experimental type 1 diabetes (T1D).Methods and resultsM-mode echocardiography established a cardiomyopathy in 8 weeks STZ-diabetic rats. Confocal microscopy confirmed an increase in the spontaneous Ca2+ release in isolated ventricular myocytes. Western blots revealed no significant change in steady-state levels of the RyR2 protein. When purified to homogeneity and incorporated into planar lipid bilayers, RyR2 from STZ-diabetic rats (dRyR2) exhibited reduced current amplitude at ±35 mV. dRyR2 was also more responsive to intrinsic cytoplasmic activators Ca2+, adenosine triphosphate, and cyclic adenosine diphosphate ribose and less responsive to the cytoplasmic deactivator Mg2+. Threshold for the activation of RyR2 by trans (luminal) Ca 2+ was also reduced. These changes were independent of phosphorylation at Ser2808 and Ser2814. Two weeks of insulin treatment starting after 6 weeks of diabetes blunted the phenotype change, indicating that the gain of function is specific to the diabetes and not the result of STZ interacting directly with RyR2.ConclusionThese data show, for the first time, that RyR2 is acquiring a gain-of-function phenotype independent of its phosphorylation status during T1D and provides new insights for the enhanced spontaneous Ca 2+ release in myocytes from T1D rats.

Original languageEnglish (US)
Pages (from-to)300-309
Number of pages10
JournalCardiovascular Research
Volume91
Issue number2
DOIs
Publication statusPublished - Jul 15 2011
Externally publishedYes

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Keywords

  • Cardiac ryanodine receptor
  • Diabetic cardiomyopathy
  • Gain of function
  • Type 1 diabetes

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Tian, C., Hong Shao, C., Moore, C. J., Kutty, S., Walseth, T., Desouza, C., & Bidasee, K. R. (2011). Gain of function of cardiac ryanodine receptor in a rat model of type 1 diabetes. Cardiovascular Research, 91(2), 300-309. https://doi.org/10.1093/cvr/cvr076