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

Modulating cytoplasmic Ca.sup.2+ concentration ([Ca.sup.2+].sub.i) by endoplasmic reticulum (ER)-localized inositol 1,4,5-trisphosphate receptor (InsP.sub.3R) Ca.sup.2+-release channels is a universal signaling pathway that regulates numerous cell-physiological processes. Whereas much is known regar...

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Bibliographic Details
Published in:eLife 2020-05, Vol.9
Main Authors: Vais, Horia, Wang, Min, Mallilankaraman, Karthik, Payne, Riley, McKennan, Chris, Lock, Jeffrey T, Spruce, Lynn A, Fiest, Carly, Chan, Matthew Yan-lok, Parker, Ian, Seeholzer, Steven H, Foskett, J Kevin, Mak, Don-On Daniel
Format: Article
Language:English
Subjects:
Annexins
Biotechnology industries
Inositol
Physiological aspects
Protein binding
Scientific equipment industry
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Summary:Modulating cytoplasmic Ca.sup.2+ concentration ([Ca.sup.2+].sub.i) by endoplasmic reticulum (ER)-localized inositol 1,4,5-trisphosphate receptor (InsP.sub.3R) Ca.sup.2+-release channels is a universal signaling pathway that regulates numerous cell-physiological processes. Whereas much is known regarding regulation of InsP.sub.3R activity by cytoplasmic ligands and processes, its regulation by ER-luminal Ca.sup.2+ concentration ([Ca.sup.2+].sub.ER) is poorly understood and controversial. We discovered that the InsP.sub.3R is regulated by a peripheral membrane-associated ER-luminal protein that strongly inhibits the channel in the presence of high, physiological [Ca.sup.2+].sub.ER. The widely-expressed Ca.sup.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.sup.2+].sub.ER inhibition of InsP.sub.3R activity. Genetic knockdown of ANXA1 expression enhanced global and local elementary InsP.sub.3-mediated Ca.sup.2+ signaling events. Thus, [Ca.sup.2+].sub.ER is a major regulator of InsP.sub.3R channel activity and InsP.sub.3R-mediated [Ca.sup.2+].sub.i signaling in cells by controlling an interaction of the channel with a peripheral membrane-associated Ca.sup.2+-binding protein, likely ANXA1.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.53531