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

Ca2+ tunneling is a signaling modality that requires both Store-operated Ca2+ entry (SOCE) and Ca2+ release from the endoplasmic reticulum (ER). Tunneling expands the SOCE microdomain at ER-plasma membrane (PM) contact sites (ERPMCS) through Ca2+ uptake by the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) into the ER lumen where it diffuses and is released via open inositol trisphosphate (IP3) receptors (IP3Rs). In this study using high resolution imaging, we outline the spatial remodeling of the Ca2+ tunneling machinery (IP3R1; 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 Ca2+ signaling modulators to distinct subdomains laterally at the PM and axially within the cortical ER. To functionally define the role of Ca2+ tunneling, we engineered a Ca2+ tunneling attenuator (CaTAr) that blocks tunneling without affecting Ca2+ release or SOCE. CaTAr inhibits Cl- secretion in sweat gland cells. Viral mediated expression of CaTAr in the mouse reduces sweating, showing that Ca2+ tunneling is important physiologically. Collectively our findings outline the architecture of the Ca2+ tunneling machinery and show that it is a fundamental physiological pertinent Ca2+ signaling modality.