Abstract
Cell survival and normal cell function require a highly coordinated and precise regulation of basal cytosolic Ca2+ concentrations. The primary source of Ca2+ entry into the cell is mediated by the Ca2+ release-activated Ca2+ (CRAC) channel. Its action is stimulated in response to internal Ca2+ store depletion. The fundamental constituents of CRAC channels are the Ca2+ sensor, stromal interaction molecule 1 (STIM1) anchored in the endoplasmic reticulum, and a highly Ca2+-selective pore-forming subunit Orai1 in the plasma membrane. The precise nature of the Orai1 pore opening is currently a topic of intensive research. This review describes how Orai1 gating checkpoints in the middle and cytosolic extended transmembrane regions act together in a concerted manner to ensure an opening-permissive Orai1 channel conformation. In this context, we highlight the effects of the currently known multitude of Orai1 mutations, which led to the identification of a series of gating checkpoints and the determination of their role in diverse steps of the Orai1 activation cascade. The synergistic action of these gating checkpoints maintains an intact pore geometry, settles STIM1 coupling, and governs pore opening. We describe the current knowledge on Orai1 channel gating mechanisms and summarize still open questions of the STIM1–Orai1 machinery.
Highlights
IntroductionAmong a huge diversity of Ca2+ ion channels, those involved in the so-called store-operated Ca2+ entry (SOCE) play a considerable role in a variety of cell types
Ca2+ releaseactivated Ca2+ (CRAC) channels are composed of two molecular key components, the endoplasmic reticulum (ER) membraneembedded stromal interaction molecule (STIM) that acts as the Ca2+ sensor and the poreforming Orai protein located in the plasma membrane (Figure 1A,B)
We recently demonstrated that the series of checkpoints can be classified on the basis of their functional roles and location into two groups: those located in the middle transmembrane region (MTR) and those located in the cytosolic extended transmembrane region (CETR) (Table 1 and Figure 4)
Summary
Among a huge diversity of Ca2+ ion channels, those involved in the so-called store-operated Ca2+ entry (SOCE) play a considerable role in a variety of cell types. They are activated upon Ca2+ store depletion of the endoplasmic reticulum (ER). Anomalous cytosolic Ca2+ concentrations, caused by either gain- (GoF) or loss-of-function (LoF) point mutations in the CRAC channel components, can lead to severe diseases such as York and Stormorken syndrome and tubular aggregate myopathy [4], severe combined immunodeficiency, autoimmunity, ectodermal dysplasia, and muscular hypotonia [5,6,7,8].
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