The skeletal muscle Ca2+ release channel, also known as the ryanodine receptor (RYR1), regulatesthe release of Ca2+ from sarcoplasmic reticulum (SR) stores and is mutated in human central coredisease (CCD) and in the pharmacogenetic syndrome, malignant hyperthermia (MH). Themutations cluster in three regions of RYR1: region 1 from amino acids 35 to 614, region 2 from2163 to 2459 and region 3 from 4647-4914. The MH mutations are located primarily in cytoplasmicregionsl and 2 while most of the CCD mutations are found in the transmembrane region 3. Theworking hypotheses to be tested in this project are: a. Regions 1 and 2, located in the clampdomain, interact to allosterically stabilize a closed state of the channel, b. The MH mutations, bydestabilizing this interaction, enhance the response of the channel (and hence muscle) to activatorsand elevated temperature, c. Enhanced RyR1 activity during exercise elevates endogenouscytokines that act as pyrogens (such as IL-6) and the subsequent increase in body temperatureincreases the probability of an MH response. To test these hypotheses, the following specific aimsare proposed: A1. Define the effects of the MH/CCD mutations on the conformational changes inthe clamp domain of RyR1 A2. Evaluate the effects of the MH/CCD mutations on the structural andcontractile properties of the muscle. A3. Determine if the probability of exercise-induced MHresponses and/or rhabdomyolysis is increased by elevated body temperature and/or increasedendogenous IL-6 concentrations. These studies will use mice with MH/CCD mutations that havebeen generated in Projects 1 and 3.
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