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.
Competing Interests: HV, MW, KM, RP, CM, JL, LS, CF, MC, IP, SS, JF, DM No competing interests declared
(© 2020, Vais et al.)