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Ca2+ entry through store-operated Ca2+ release-activated Ca2+ (CRAC) channels plays a central role in activation of a range of cellular responses over broad spatial and temporal bandwidths. Mitochondria, through their ability to take up cytosolic Ca2+ , are important regulators of CRAC channel activity under physiological conditions of weak intracellular Ca2+ buffering. The mitochondrial Ca2+ transporter(s) that regulates CRAC channels is unclear and could involve the 40 KDa mitochondrial Ca2+ uptake channel MCU or the Na+ -Ca2+ -Li+ exchanger (NCLX). Here, we have investigated the involvement of these mitochondrial Ca2+ transporters in supporting the CRAC current ICRAC under a range of conditions in RBL mast cells. Knockdown of the MCU impaired the activation of ICRAC under physiological conditions of weak intracellular Ca2+ buffering. In strong Ca2+ buffer, knockdown of the MCU channel did not inhibit ICRAC development demonstrating that mitochondria regulate CRAC channels under physiological conditions by buffering of cytosolic Ca2+ via the MCU channel. Surprisingly, manipulations that altered extracellular Na+ , cytosolic Na+ or both failed to inhibit the development of ICRAC in either strong or weak intracellular Ca2+ buffer. Knockdown of NCLX also did not affect ICRAC . Prolonged removal of external Na+ also had no significant effect on store-operated Ca2+ entry, on cytosolic Ca2+ oscillations generated by receptor stimulation or on CRAC channel-driven gene expression. In the RBL mast cell, Ca2+ flux through the MCU but not NCLX is indispensable for activation of ICRAC . This article is protected by copyright. All rights reserved.

Original publication

DOI

10.1113/jp276551

Type

Journal article

Journal

The Journal of Physiology

Publisher

Wiley

Publication Date

24/12/2018

Volume

00

Pages

1 - 21

Addresses

Department of Physiology, Anatomy and Genetics, Oxford University, Sherrington Building, Parks Road, Oxford, OX1 3PT, UK.