Abstract 954: Stim1/orai1 Signaling Controls Store Operated Calcium Entry Required For Signaling And Contractile Function In Smooth And Striated Muscle
It is now well established that stromal interaction molecule 1 (STIM1) is the calcium sensor of endoplasmic reticulum (ER) stores required to activate store operative calcium entry (SOCE) channels at the surface of non-excitable cells. Yet little is known about STIM1 in excitable cells such as striated muscle where the complement of calcium regulatory molecules is rather disparate from that of non-excitable cells. Here, we show that STIM1 is expressed in smooth, cardiac and skeletal muscle. Mice carrying LacZ reporter gene under the control of the endogenous promoter for STIM1 demonstrate STIM1 expression in the select cells of heart, neonatal and adult muscle fibers and smooth muscles layers of the aorta. Myocytes (smooth and skeletal muscle) isolated from STIM1 mutant mice fail to develop SOCE following store depletion and fail to exhibit store operative currents induced by thapsigargin. Myocytes lacking functional STIM1 also fatigue rapidly, and surprisingly mice lacking a functional STIM1 die perinatally with skeletal myopathy as was evident by transmission electron microscopy and biochemical analysis of muscle proteins (SERCA1 and myosin heavy chain). In addition, STIM1 haploinsuffiency confers a contractile defect of isolated skeletal muscle only under conditions of increased demand where refilling of stores would be needed. These findings provide novel insight to the role of STIM1 in excitable cells and suggest a more universal role for STIM1 as a calcium sensor of internal stores for both excitable and non-excitable stores.