ER-luminal [Ca(2+)] regulation of InsP(3) receptor gating mediated by an ER-luminal peripheral Ca(2+)-binding protein

Modulating cytoplasmic Ca(2+) concentration ([Ca(2+)](i)) by endoplasmic reticulum (ER)-localized inositol 1,4,5-trisphosphate receptor (InsP(3)R) Ca(2+)-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 Ca(2+) concentration ([Ca(2+)](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 [Ca(2+)](ER). The widely-expressed Ca(2+)-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-[Ca(2+)](ER) inhibition of InsP(3)R activity. Genetic knockdown of ANXA1 expression enhanced global and local elementary InsP(3)-mediated Ca(2+) signaling events. Thus, [Ca(2+)](ER) is a major regulator of InsP(3)R channel activity and InsP(3)R-mediated [Ca(2+)](i) signaling in cells by controlling an interaction of the channel with a peripheral membrane-associated Ca(2+)-binding protein, likely ANXA1.