Abstract
STIM1, a Ca2+-sensing protein on ER/SR membrane, mediates a store-operated Ca2+-entry (SOCE) by activating Orai1 Ca2+-entry channel on plasma membrane. E136X mutant of STIM1, truncated STIM1 missing binding abilities to Orai1, has been found in patients with immunodeficiency accompanying muscular hypotonia. To identify causes of the muscular hypotonia, E136X was expressed in mouse skeletal myotubes and dominant-negative effects of E136X were examined. Myotubes expressing E136X showed increases in both KCl (a membrane depolarizer resulting excitation-contraction coupling) and caffeine (a direct RyR1 agonist) responses. On the other hand, SOCE, resting cytosolic Ca2+ level, SR Ca2+ level were not significantly changed by the expression of E136X. In addition, E136X did not interfere with puncta formations by endogenous STIM1 and Orai1. These data mean that muscular hypotonia found in patients with E136X is due to changes in excitation-contraction coupling. Additionally, we suggest that C-terminus of STIM1 that is missing in E136X participates in the regulation of skeletal EC coupling.
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