Regulation of Calcium Release by Calmodulin in Muscle

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DESCRIPTION (provided by applicant): Alterations in skeletal muscle sarcoplasmic reticulum (SR) calcium (Ca2+) release via the ryanodine receptor (RYR) Ca2+ release channel have been identified in a number of muscle diseases including malignant hyperthermia and central core disease. The regulation of SR Ca2+ release by endogenous ligands is also altered in these diseased muscles. This signifies the importance of understanding the regulation of RYR activity by endogenous modulators. Techniques utilizing laser scanning confocal microscopy and the Ca2+ indicator Fluo-3 have allowed the imaging of discrete localized Ca2+ release events (Ca2+ sparks) in functionally intact skeletal muscle. Examination of properties and frequency of occurrence of these events in response to either voltage or ligand stimulation is providing insight into the molecular control of SR Ca2+ release within the context of the functioning muscle fiber. The main objective of this proposal is to examine the modulation of the local control of SR Ca2+ release by calmodulin in functionally intact skeletal muscle fibers. Specifically, I intend to examine the effects of calmodulin on spontaneous and voltage activated skeletal muscle Ca2+ spark properties to gain insight into the role calmodulin plays in skeletal muscle excitation contraction coupling. The use of recombinant calmodulin, both wild type and a mutant that cannot bind Ca2+, will allow for the assessment of the role calmodulin plays in the activation, propagation and termination of these discrete localized Ca2+ release events.