The overall goal of this project is to identify cellular and molecular triggers that promote heart failure (HF) and to determine novel molecular-targeted therapeutic strategies to treat them. The central hypothesis is that HF can be caused by disruption of molecular signaling complexes and processes that, in normal hearts, underlie balanced regulation of cellular activity and furthermore that altered cellular calcium (Ca) homeostasis plays a critical role in HF progression. This project focuses on elucidating defects in the regulation of type 2 ryanodine receptor (RyR2)/Ca release channel, which is required for cardiac excitation- contraction (EC) coupling. We propose to test the hypothesis that a diastolic SR Ca """"""""leak"""""""" via defective RyR2 can contribute to SR Ca depletion and impaired contractility in HF. During the previous funding period of this project the applicant identified a defect in RyR2 in patients with HF: """"""""leaky"""""""" PKA hyperphosphorylated RyR2 channels that exhibit decreased binding affinity for the stabilizing subunit calstabini (FKBP12.6). This observation has directly lead to the development of a novel potential therapy for HF, RyCal (JTV-S36, which is a JTV-519 derivative without HERG and L-type channel blocking activities), representing a new class of intracellular calcium channel stabilizers that improve cardiac function in murine and canine HF models. The applicant has recently identified the phosphodiesterase PDE4D3 as a novel component of the RyR2 complex and preliminary data, presented in this proposal, suggest that PDE4D3 in the RyR2 complex may be """"""""protective"""""""" against HF because mice that are deficient in PDE4D3 are predisposed to HF following Ml. Moreover, mice engineered to express an RyR2 channel that cannot be PKA phosphorylated, RyR2- S2808A, are protected against HF following myocardial infarction (Ml). Three new aims are proposed: 1) Using RyR2-S2808A and RyR2-S2808D """"""""knock-in"""""""" mice that have RyR2 channels that either cannot be PKA phosphorylated or that mimic constitutively PKA phosphorylated RyR2 channels respectively, we will determine the role of PKA phosphorylation of RyR2 in regulating cardiac contractility and in HF progression;2) preliminary data show that in HF the amount of phosphodiesterase 4D3 (PDE4D3) and the phosphatase PP1 in the RyR2 complex is decreased, we will determine the mechanisms regulating the targeting of PDE4D3 and PP1 to the RyR2 complex;3) the role of skeletal muscle fatigue in HF has been poorly understood, we will use muscle-specific calstabin1 and calstabin2 deficient mouse models to determine how specifically improving skeletal muscle function versus improving cardiac muscle function affects the progression of HF following Ml and we will use RyR1-S2843D mice that mimic constitutively PKA phosphorylated RyR1 in skeletal muscle to determine how having constitutively """"""""leaky"""""""" skeletal muscle RYR1 affects HF progression. The proposed studies are significant because they will provide novel insights concerning the mechanisms of HF progression.
| Kushnir, Alexander; Santulli, Gaetano; Reiken, Steven R et al. (2018) Ryanodine Receptor Calcium Leak in Circulating B-Lymphocytes as a Biomarker in Heart Failure. Circulation 138:1144-1154 |
| Hartel, Andreas J W; Ong, Peijie; Schroeder, Indra et al. (2018) Single-channel recordings of RyR1 at microsecond resolution in CMOS-suspended membranes. Proc Natl Acad Sci U S A 115:E1789-E1798 |
| Santulli, Gaetano; Lewis, Daniel; des Georges, Amedee et al. (2018) Ryanodine Receptor Structure and Function in Health and Disease. Subcell Biochem 87:329-352 |
| Lacampagne, Alain; Liu, Xiaoping; Reiken, Steven et al. (2017) Post-translational remodeling of ryanodine receptor induces calcium leak leading to Alzheimer's disease-like pathologies and cognitive deficits. Acta Neuropathol 134:749-767 |
| Bussiere, Renaud; Lacampagne, Alain; Reiken, Steven et al. (2017) Amyloid ? production is regulated by ?2-adrenergic signaling-mediated post-translational modifications of the ryanodine receptor. J Biol Chem 292:10153-10168 |
| Zalk, Ran; Marks, Andrew R (2017) Ca2+ Release Channels Join the 'Resolution Revolution'. Trends Biochem Sci 42:543-555 |
| Santulli, Gaetano; Lewis, Daniel R; Marks, Andrew R (2017) Physiology and pathophysiology of excitation-contraction coupling: the functional role of ryanodine receptor. J Muscle Res Cell Motil 38:37-45 |
| Yuan, Qi; Yang, Jingyi; Santulli, Gaetano et al. (2016) Maintenance of normal blood pressure is dependent on IP3R1-mediated regulation of eNOS. Proc Natl Acad Sci U S A 113:8532-7 |
| des Georges, Amédée; Clarke, Oliver B; Zalk, Ran et al. (2016) Structural Basis for Gating and Activation of RyR1. Cell 167:145-157.e17 |
| Zalk, Ran; Clarke, Oliver B; des Georges, Amédée et al. (2015) Structure of a mammalian ryanodine receptor. Nature 517:44-9 |
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