Structure-Function of Calcium Channel Complexes in Cardiac Physiology and Disease

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SUMMARY Heart disease is the leading cause of death in the United States and worldwide, with a worsening trajectory due to increasingly aging populations. Precise understanding of the molecular mechanisms underlying normal cardiac physiology, and how they are compromised in disease, is critical for identifying new drug targets and developing effective new therapeutics to combat heart disease. Ca2+ cycling involving local signaling between surface L-type Ca2+ (CaV1.2) channels and intracellular ryanodine receptors (RYR2) is responsible for the Ca2+- induced Ca2+ release (CICR) that underlies cardiac excitation-contraction coupling. Dysregulation of both CaV1.2 and RYR2 contributes to abnormal calcium signaling that is an adverse hallmark of cardiac disease. β-adrenergic augmentation of cardiac contractility is crucial for the fight-or-flight response and is mediated by increased CaV1.2 current and sensitization of RYR2; yet, excessive activation of this pathway under chronic stress results in post- translational modifications of RYR2 channels that cause them to become ‘leaky’ and cause cardiac pathology, and also a potential harmful subcellular redistribution of CaV1.2. There are significant gaps in knowledge regarding CaV1.2 and RYR2 functional organization and regulation in heart under both and disease conditions; how their dysregulation or dysfunction contributes to heart disease progression; and whether and how they can be targeted for effective treatment of heart failure (HF) and other cardiac diseases. This Program Project Grant (PPG) comprises four Projects and two Scientific Cores that have been put together to help address these critical gaps. The overarching goal is to define the mechanisms that regulate local Ca2+ signaling by CaV1.2 and RYR2 in normal and failing hearts with unprecedented precision. While each project stands on its own footing as far as being comprised of innovative and exciting research, all are dependent on the expertise provided by the Cores and are enriched by interproject collaborations that are greatly enhanced by the PPG structure. All four Projects leverage the Pakistan Genome Resource (PGR) (Core A), a unique cohort of individuals with extensive phenotype and genotype data on HF and other cardiac diseases and high rates of consanguinity enabling identification of individuals homozygous for rare truncating mutations (i.e., human knockouts) and other missense variants. Moreover, all four Projects involve experiments that span fundamental studies on single molecules and cells to animal models (Core B; Mouse Cardiac Physiology Core). Combining human missense / loss of function mutations found in the PGR cohort in CaV1.2, RYR2 or key regulatory proteins with in-depth structure-function experiments promises to advance new understanding of genotype-phenotype relationships in human cardiovascular diseases involving Ca2+ cycling proteins in the heart. We expect the proposed studies to yield new insights into structure-function and regulation of CaV1.2 and RYR2 and advance their utility as therapeutic targets for cardiac dysfunction. The PIs of the four projects have a collaboration history and track record of developing innovative approaches for studies of CaV1.2 and RYR2 molecular physiology.