Calmodulin & Calmodulin Binding Domains in E-C Coupling

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DESCRIPTION (provided by applicant): The candidate, George Rodney, Ph.D., is a physiologist who has been funded by an Individual NRSA and is currently a Research Associate in the Department of Biochemistry & Molecular Biology at the University of Maryland. His career goal is to develop a productive, independent, extramurally funded laboratory, the focus of which will be to study the basic mechanisms of E-C coupling in both normal and pathological muscle. The proposed Mentored Research Scientist Development Award will provide the necessary professional and research skills needed to achieve these goals. The general goal of this proposal is to critically examine the role of calmodulin (CaM) and the CaM binding domains within the voltage dependent L-type Ca2+ channel (DHPR) and the skeletal muscle sarcoplasmic reticulum Ca2+ release channel (ryanodine receptor, RyR) in modulating skeletal muscle excitation-contraction coupling. Both the DHPR and RyR contain binding sites for the ubiquitous Ca2+ binding protein CaM and RyR is functionally modulated by CaM. Furthermore, recent data suggest that the mechanical coupling between the DHPR and RyR may occur, in part, through their CaM binding domains. To elucidate the role of CaM in the modulation of Ca2+ mobilization in skeletal muscle three specific aims are proposed. 1) Examine the role of calmodulin in modulating voltage activated versus Ca2+ activated SR Ca2+ release. 2) Examine the RyR isoform dependence of calmodulin's modulation of SR Ca2+ release. 3) Characterize the contribution of calmodulin binding domains within the DHPR and RyR on SR Ca2+ release and E-C coupling. This research will be conducted at the University of Maryland School of Medicine, which houses nationally and internationally renowned scientist studying Ca2+ signaling in muscle as well as state-of-the-art facilities in fluorescent confocal microscopy. The sponsor, Martin Schneider Ph.D., is an established investigator in muscle research and is the director of a NIH-NIAMS funded training program in muscle biology. Under the expert guidance of Dr. Schneider and his Advisory Committee of senior investigators Dr. Rodney will develop the necessary professional and research skills needed to lead an outstanding and productive career in skeletal muscle biology.