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

Author:

Vais Horia1,Wang Min1,Mallilankaraman Karthik1ORCID,Payne Riley1,McKennan Chris2,Lock Jeffrey T3ORCID,Spruce Lynn A4,Fiest Carly1ORCID,Chan Matthew Yan-lok1,Parker Ian35,Seeholzer Steven H4,Foskett J Kevin16ORCID,Mak Don-On Daniel1ORCID

Affiliation:

1. Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States

2. Department of Statistics, University of Pittsburgh, Pittsburgh, United States

3. Department of Neurobiology and Behavior, University of California, Irvine, United States

4. Proteomics Core Facility, The Children’s Hospital of Philadelphia, Philadelphia, United States

5. Department of Physiology and Biophysics, University of California, Irvine, United States

6. Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States

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.

Funder

National Institutes of Health

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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