Architecture of Ca2+tunneling, a basic Ca2+signaling modality important for secretion

ABSTRACT Ca 2+ tunneling is a signaling modality that requires both Store-operated Ca 2+ entry (SOCE) and Ca 2+ release from the endoplasmic reticulum (ER). Tunneling expands the SOCE microdomain at ER-plasma membrane (PM) contact sites (ERPMCS) through Ca 2+ uptake by the sarco/endoplasmic reticulum Ca 2+ ATPase (SERCA) into the ER lumen where it diffuses and is released via open inositol trisphosphate (IP 3 ) receptors (IP 3 Rs). In this study using high resolution imaging, we outline the spatial remodeling of the Ca 2+ tunneling machinery (IP 3 R1; SERCA; PMCA; and Ano1 as an effector) relative to STIM1 in response to store depletion. We show that store depletion leads to redistribution of these Ca 2+ signaling modulators to distinct subdomains laterally at the PM and axially within the cortical ER. To functionally define the role of Ca 2+ tunneling, we engineered a Ca 2+ tunneling attenuator (CaTAr) that blocks tunneling without affecting Ca 2+ release or SOCE. CaTAr inhibits Cl − secretion in sweat gland cells. Viral mediated expression of CaTAr in the mouse reduces sweating, showing that Ca 2+ tunneling is important physiologically. Collectively our findings outline the architecture of the Ca 2+ tunneling machinery and show that it is a fundamental physiological pertinent Ca 2+ signaling modality.