ER-luminal [Ca2+] regulation of InsP3 receptor gating mediated by an ER-luminal peripheral Ca2+-binding protein

Modulating cytoplasmic Ca2+ concentration ([Ca2+](i)) by endoplasmic reticulum (ER)localized inositol 1,4,5-trisphosphate receptor (InsP(3)R) Ca2+-release channels is a universal signaling pathway that regulates numerous cell-physiological processes. Whereas much is known regarding regulation of InsP(3)R activity by cytoplasmic ligands and processes, its regulation by ER-luminal Ca2+ concentration ([Ca2+]ER) is poorly understood and controversial. We discovered that the InsP(3)R is regulated by a peripheral membrane-associated ER-luminal protein that strongly inhibits the channel in the presence of high, physiological [Ca2+]ER. The widely-expressed Ca2+-binding protein annexin A1 (ANXA1) is present in the nuclear envelope lumen and, through interaction with a luminal region of the channel, can modify high-[Ca2+]ER inhibition of InsP(3)R activity. Genetic knockdown of ANXA1 expression enhanced global and local elementary InsP(3)-mediated Ca2+ signaling events. Thus, [Ca2+]ER is a major regulator of InsP(3)R channel activity and InsP(3)R-mediated [Ca2+]i signaling in cells by controlling an interaction of the channel with a peripheral membrane-associated Ca2+-binding protein, likely ANXA1.