E-C coupling efficiency in hibernation and heart failure

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DESCRIPTION (provided by applicant): While the efficiency of cardiac excitation-contraction (E-C) coupling in heart failure undergoes a defective down-regulation, that in hibernating mammals is up-regulated. The long-term objective of the proposed research is to find the cellular and molecular mechanism of E-C coupling regulation in hibernators, and seek to apply them in rescuing failing hearts. The specific aims, hypotheses and research designs are: 1) to test the hypothesis that the Ca2+ influx tends to activate more Ca2+ release from sarcoplasmic reticulum hibernating than awake hibernators such that the E-C coupling efficiency can be increased. This will be achieved by combining electrophysiological recording and confocal Ca2+ imaging. 2) to test the hypothesis that, in a single E-C coupling unit, Ca2+ release channels become more responsive to single-channel Ca2+ trigger during hibernation, but less in impaired E-C coupling during heart failure. The intermolecular coupling fidelity and latency and signal mass of Ca2+ sparks in failing and hibernating models will be analyzed using our recently developed loose-patch confocal imaging. 3) to test the hypothesis that different changes in the unitary properties of Ca2+ underlie the opposite alternation of E-C coupling efficiency in hibernation and heart failure. The strength and kinetics of single-channel Ca2+ release and micro-recruitment of release channels in failure and hibernation models will be assessed by analyzing the quantal property of Ca2+ sparks recently found by this PI. The above study will reveal the molecular details underlying the opposite modifications of E-C coupling occurred in hibernation and heart failure. This will provide necessary and important basis for further studies to rescue failing heart with strategies employed by hibernators.