Regulation of Sarcoplasmic Reticulum Calcium Release in Heart Failure

$396,250R01FY2018HLNIH

Baylor College Of Medicine, Houston TX

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Abstract

? DESCRIPTION (provided by applicant): It is well established that altered sarcoplasmic reticulum (SR) Ca handling plays a key role in HF pathogenesis. Whereas altered post-translational modifications (PTM) of the SR Ca release channel/ ryanodine receptor type- 2 (RyR2) have been linked to HF development, it remains highly controversial which kinases and phosphatases underlie these disease-associated changes. RyR2 hyper-phosphorylation can be caused by increased activity of protein kinase A (PKA) and Ca/calmodulin-dependent protein kinase II (CaMKII). However, there remains significant controversy about the mechanisms underlying altered phosphorylation of RyR2 in HF. We have identified a novel kinase within the RyR2 macromolecular complex, known as `striated muscle preferentially expressed gene' (SPEG). Our preliminary data show that SPEG phosphorylates a novel phosphorylation site on RyR2, S2811. In addition, our data suggest that SPEG levels are downregulated in patients and mice with congestive heart failure. Our long-term goal is to define the molecular and cellular mechanisms by which SEPG regulates RyR2 and intracellular Ca handling in normal and failing hearts. The overall hypothesis is that SPEG phosphorylates a novel S2811 residue on RyR2, which modulates RyR2 activity and intracellular Ca handling in cardiac myocytes. Specific aim (1) will determine how SPEG binds to RyR2 and how SPEG modifies intracellular Ca handling. Specific aim (2) will assess the role of SPEG modulation of RyR2 in heart failure. Specific aim (3) will determine the role of SPEG-mediated phosphorylation of S2811 on RyR2 in normal and failing hearts. Significance: Heart failure (HF) is a deadly and costly disease affecting 5.7 millin people in the US alone, and a leading cause of hospitalization for those >65 years of age. A better understanding of the molecular mechanisms underlying abnormal RyR2 function in HF could lead to new pharmacological strategies.

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