Mechanism of Calcium Regulation in Striated Muscle

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DESCRIPTION (provided by applicant): Muscle contraction is one of the fundamental biological processes. In spite of many years of intense research, the two major questions, the mechanisms of force generation and its regulation, remain incompletely understood. The long term objective of this project is to decipher the molecular mechanism for the regulation of striated (skeletal and cadiac) muscle contraction via Ca 2+, troponin and tropomyosin. The specific aims for this proposal are: 1) To decipher the mechanism whereby attachment of troponin I to actin inhibits muscle contraction in the absence of Ca2+. 2) To decipher the mechanism whereby the movement of tropomyosin in the F-actin filament gives rise to inhibition or activation of muscle contrction. 3) To determine the functional role of troponin T in thin filament regulation. The principal techniques will be site-directed mutagenesis, disulfide crosslinking, photocrosslinking and Forster resonance energy transfer (FRET). The results will make major contributions not only to the muscle field, but also to areas in signal transduction that involve regulation by Ca 2+. Findings derived from this project will be relevant to the prevention, diagnosis and cure of certain neuromuscular diseases. Cardiac and skeletal muscle thin filament proteins share a great deal of similarity in amino acid sequence and function. Cardiac Tn subunits have been used as markers for heart failure. Point mutations in the cardiac thin filament proteins have been implicated in certain cardiomyopathies. Thus our findings here will also be relevant to ischemic infarction and familial hypertrophic cardiomyopathy.