Release of calcium ions from the sarcoplasmic reticulum via type 2 ryanodine receptors (RyR2) is an integral step in the cascade of events leading to cardiac muscle contraction. Studies have shown that this process is compromised in heart of diabetic rats (Yu and McNeill 1991; Yu et al. 1994). We recently found that the decrease in activity of RyR2 stems from a dysfunction of this protein rather than a decrease its expression (Bidasee et al manuscript #1). To date, the molecular basis for the dysfunction of RyR2 is not known. Our working hypothesis is """"""""diabetes alters the integrity of the calcium efflux pathway on RyR2."""""""" In this project we want to characterize changes in RyR2 induced by diabetes and to determine the effects of these changes on the regulation of RyR2 by endogenous modulators. At the same time, we want to investigate whether the beneficial effects of insulin and verapamil treatments include reversal of diabetes-induced changes to RyR2 protein.
Our specific aims are: (1) to identify and characterize molecular changes to RyR2 protein induced by diabetes, (2) to ascertain whether these changes alter the sensitivity of RyR2 to endogenous modulators like Ca2+, pH etc., (3) to determine whether changes to RyR2 induced by long-term diabetes can be reversed with insulin treatment, (4) to determine whether verapamil treatment can protect and/or reverse diabetes-induced changes to RyR2, and (5) to establish if verapamil and insulin co-treatments have additive effects on reversing changes to RyR2 induced by diabetes. Accomplishment of these aims will contribute significantly to understanding the molecular basis for the decrease activity of RyR2 protein (and possibly other proteins) in diabetes and this could lead to newer insights into therapeutic strategies for alleviating diabetes-induced dysfunction of the heart.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZHL1-CSR-Y (S2))
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Liang, Isabella Y
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Indiana University-Purdue University at Indianapolis
Schools of Medicine
United States
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Moore, Caronda J; Shao, Chun Hong; Nagai, Ryoji et al. (2013) Malondialdehyde and 4-hydroxynonenal adducts are not formed on cardiac ryanodine receptor (RyR2) and sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2) in diabetes. Mol Cell Biochem 376:121-35
Guner, Sahika; Arioglu, Ebru; Tay, Aydin et al. (2004) Diabetes decreases mRNA levels of calcium-release channels in human atrial appendage. Mol Cell Biochem 263:143-50
Hui, Chiu Shuen; Besch Jr, Henry R; Bidasee, Keshore R (2004) Effects of ryanoids on spontaneous and depolarization-evoked calcium release events in frog muscle. Biophys J 87:243-55
Bidasee, Keshore R; Zhang, Yinong; Shao, Chun Hong et al. (2004) Diabetes increases formation of advanced glycation end products on Sarco(endo)plasmic reticulum Ca2+-ATPase. Diabetes 53:463-73
Bidasee, Keshore R; Xu, Le; Meissner, Gerhard et al. (2003) Diketopyridylryanodine has three concentration-dependent effects on the cardiac calcium-release channel/ryanodine receptor. J Biol Chem 278:14237-48
Zhang, Yinong; Cocklin, Ross R; Bidasee, Keshore R et al. (2003) Rapid determination of advanced glycation end products of proteins using MALDI-TOF-MS and PERL script peptide searching algorithm. J Biomol Tech 14:224-30
Bidasee, Keshore R; Nallani, Karuna; Yu, Yongqi et al. (2003) Chronic diabetes increases advanced glycation end products on cardiac ryanodine receptors/calcium-release channels. Diabetes 52:1825-36
Bidasee, Keshore R; Nallani, Karuna; Besch Jr, Henry R et al. (2003) Streptozotocin-induced diabetes increases disulfide bond formation on cardiac ryanodine receptor (RyR2). J Pharmacol Exp Ther 305:989-98
Bidasee, Keshore R; Nallani, Karuna; Henry, Bruce et al. (2003) Chronic diabetes alters function and expression of ryanodine receptor calcium-release channels in rat hearts. Mol Cell Biochem 249:113-23
Gersting, J A; Bidasee, K R; Dincer UD et al. (2001) Determination of complement of mRNA encoding inositol 1,4,5-trisphosphate receptor isoforms in rat tissues using relative-polymerase chain reaction. Anal Biochem 294:188-90

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