The Function of Stromal Interaction Molecule 1 (STIM1) in Heart

Stromal interaction molecule 1 (STIM1), an ER/SR Ca2+ sensor, has been well described as an activator of store-operated calcium channel (SOCC) Orai1 or the equivalents, upon SR/ER (Sarco/endoplasmic reticulum) Ca2+ depletion in many cell types. In heart, however, we found that the canonical actions of STIM1 do not apply. For example, STIM1 appears to be organized in puncta and linear segments apparently at the junctional SR (jSR) whether or not the SR is loaded with Ca2+. In normal ventricular myocytes the mobility of STIM1 was not changed by SR Ca2+ load when evaluated by fluorescence recovery after photobleaching (FRAP). Furthermore, in ventricular myocytes, STIM1 function does not depend on Orai1 while in sinoatrial node (SAN) cells, it does. In the ventricular myocytes, we found that STIM1 binds to non-phosphorylated phospholamban, an endogenous inhibitor of SERCA2a (Sarco/endoplasmic reticulum Ca2+ ATPase). By this means increased STIM1 levels activate (or “dis-inhibit”) SERCA2a in ventricular myocytes. In the SAN cells, however, STIM1 is involved in SAN automaticity regulation through Orai1 (and possibly by other means). Consistent with these findings, STIM1 null cells show decreased SR Ca2+ content in SAN and STIM1 overexpressing cells show increased SR Ca2+ content in ventricular myocytes. We therefore conclude that in heart, STIM1 contributes to the regulation of SR Ca2+ content through binding to different partners (including Orai1 and phospholamban) in ventricular myocytes and SAN. The kinetics and more complete physiological and pathophysiological influences of STIM1 on SR Ca2+ content in heart are under active investigation.