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


ABSTRACT: Modulating cytoplasmic Ca2+ concentration ([Ca2+]i) by endoplasmic reticulum (ER)-localized inositol 1,4,5-trisphosphate receptor (InsP3R) Ca2+-release channels is a universal signaling pathway that regulates numerous cell-physiological processes. Whereas much is known regarding regulation of InsP3R activity by cytoplasmic ligands and processes, its regulation by ER-luminal Ca2+ concentration ([Ca2+]ER) is poorly understood and controversial. We discovered that the InsP3R 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 InsP3R activity. Genetic knockdown of ANXA1 expression enhanced global and local elementary InsP3-mediated Ca2+ signaling events. Thus, [Ca2+]ER is a major regulator of InsP3R channel activity and InsP3R-mediated [Ca2+]i signaling in cells by controlling an interaction of the channel with a peripheral membrane-associated Ca2+-binding protein, likely ANXA1.

SUBMITTER: Vais H 

PROVIDER: S-EPMC7259957 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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ER-luminal [Ca<sup>2+</sup>] regulation of InsP<sub>3</sub> receptor gating mediated by an ER-luminal peripheral Ca<sup>2+</sup>-binding protein.

Vais Horia H   Wang Min M   Mallilankaraman Karthik K   Payne Riley R   McKennan Chris C   Lock Jeffrey T JT   Spruce Lynn A LA   Fiest Carly C   Chan Matthew Yan-Lok MY   Parker Ian I   Seeholzer Steven H SH   Foskett J Kevin JK   Mak Don-On Daniel DD  

eLife 20200518


Modulating cytoplasmic Ca<sup>2+</sup> concentration ([Ca<sup>2+</sup>]<sub>i</sub>) by endoplasmic reticulum (ER)-localized inositol 1,4,5-trisphosphate receptor (InsP<sub>3</sub>R) Ca<sup>2+</sup>-release channels is a universal signaling pathway that regulates numerous cell-physiological processes. Whereas much is known regarding regulation of InsP<sub>3</sub>R activity by cytoplasmic ligands and processes, its regulation by ER-luminal Ca<sup>2+</sup> concentration ([Ca<sup>2+</sup>]<sub>ER</  ...[more]

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