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Review
. 2013 Sep-Oct;7(5):402-14.
doi: 10.4161/chan.25292. Epub 2013 Aug 26.

Molecular pharmacology of store-operated CRAC channels

Amit Jairaman  1 , Murali Prakriya  1
Affiliations
Review

Molecular pharmacology of store-operated CRAC channels

Amit Jairaman et al. Channels (Austin). 2013 Sep-Oct.

Abstract

Calcium influx through store-operated Ca(2+) release-activated Ca(2+) channels (CRAC channels) is a well-defined mechanism of generating cellular Ca(2+) elevations that regulates many functions including gene expression, exocytosis and cell proliferation. The identifications of the ER Ca(2+) sensing proteins, STIM1-2 and the CRAC channel proteins, Orai1-3, have led to improved understanding of the physiological roles and the activation mechanism of CRAC channels. Defects in CRAC channel function are associated with serious human diseases such as immunodeficiency and auto-immunity. In this review, we discuss several pharmacological modulators of CRAC channels, focusing specifically on the molecular mechanism of drug action and their utility in illuminating the mechanism of CRAC channel operation and their physiological roles in different cells.

Keywords: CRAC channel; Orai1; SOCE; STIM1; pharmacology.

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Figures

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Figure 3. Chemical structures of the different pharmacological inhibitors of CRAC channels. (A) 2-APB and 2-APB analogs; (B) pyrazole compounds; (C) novel pyrazole derivatives and Synta66.
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Figure 1. Topological architecture of STIM1 and Orai1 (A) Functional domains in STIM1 highlighted are: Sig, Signal peptide; SAM, sterile α-motif; TM, transmembrane; CC1-3, coiledcoiled regions; CAD, CRAC activation domain; S/P, serine-proline rich domains; K-rich, lysine rich polybasic domain. The numbers indicate residues starting from the N-terminus. (B) Functional domains in Orai1: TM1-4, trans-membrane segments of Orai1; STIM1 binding sites are highlighted in red.
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Figure 2. Crystal structure of Drosophila Orai in the closed state. (A) Cross-sectional view of Drosophila Orai from the extracellular side showing a hexameric Orai complex arranged around a central axis. The 4 trans-membrane helices of 1 subunit are highlighted in color. (B) Architecture of the Orai pore showing 2 TM1 helices. The predicted pore-lining residues in TM1 are highlighted in yellow along with their side chains. The corresponding residues for human Orai1 are shown in parentheses. Residues R155 and K159 (R83 and K87 in human Orai1) in the N-terminus that may be a part of the ion conduction pathway are highlighted in orange (adapted from ref. 88).
See this image and copyright information in PMC

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