Research ArticleCell Biology

Cholesterol modulates Orai1 channel function

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Sci. Signal.  26 Jan 2016:
Vol. 9, Issue 412, pp. ra10
DOI: 10.1126/scisignal.aad7808

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Orai1 senses cholesterol

Calcium in cells is stored in various compartments and released to initiate various cellular processes and signaling cascades. Orai proteins are the channel component of a complex that mediates the CRAC current, which mediates calcium influx into cells in response to the depletion of calcium from intracellular stores. Derler et al. found that cholesterol bound to Orai1, suppressing its activity and calcium influx. In mast cells, cholesterol depletion enhanced CRAC currents and degranulation, a process that releases inflammatory mediators such as histamine and requires increased intracellular calcium. Thus, cholesterol reduces the activity of Orai1 and calcium influx through this channel.

Abstract

STIM1 (stromal interaction molecule 1) and Orai proteins are the essential components of Ca2+ release–activated Ca2+ (CRAC) channels. We focused on the role of cholesterol in the regulation of STIM1-mediated Orai1 currents. Chemically induced cholesterol depletion enhanced store-operated Ca2+ entry (SOCE) and Orai1 currents. Furthermore, cholesterol depletion in mucosal-type mast cells augmented endogenous CRAC currents, which were associated with increased degranulation, a process that requires calcium influx. Single point mutations in the Orai1 amino terminus that would be expected to abolish cholesterol binding enhanced SOCE to a similar extent as did cholesterol depletion. The increase in Orai1 activity in cells expressing these cholesterol-binding–deficient mutants occurred without affecting the amount in the plasma membrane or the coupling of STIM1 to Orai1. We detected cholesterol binding to an Orai1 amino-terminal fragment in vitro and to full-length Orai1 in cells. Thus, our data showed that Orai1 senses the amount of cholesterol in the plasma membrane and that the interaction of Orai1 with cholesterol inhibits its activity, thereby limiting SOCE.

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