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Review
. 2015 Oct;58(4):357-67.
doi: 10.1016/j.ceca.2015.07.001. Epub 2015 Jul 17.

The STIM1-ORAI1 microdomain

Patrick G Hogan  1
Affiliations
Review

The STIM1-ORAI1 microdomain

Patrick G Hogan. Cell Calcium. 2015 Oct.

Abstract

The regulatory protein STIM1 controls gating of the Ca(2+) channel ORAI1 by a direct protein-protein interaction. Because STIM1 is anchored in the ER membrane and ORAI1 is in the plasma membrane, the STIM-ORAI pathway can support Ca(2+) influx only where the two membranes come into close apposition, effectively demarcating a microdomain for Ca(2+) signalling. This review begins with a brief summary of the STIM-ORAI pathway of store-operated Ca(2+) influx, then turns to the special geometry of the STIM-ORAI microdomain and the expected characteristics of the microdomain Ca(2+) signal. A final section of the review seeks to place the STIM-ORAI microdomain into a broader context of cellular Ca(2+) signalling.

Keywords: CRAC channel; Calcium; Microdomain; ORAI1; STIM1; Store-operated calcium entry.

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Figures

FIGURE 1
FIGURE 1
(A) STIM1 and ORAI1 colocalize after ER Ca2+ store depletion. The micrographs are optical sections at the footprint of two HeLa cells expressing GFP-STIM1 and mCherry-ORAI1. ER Ca2+ stores had been depleted by treatment with thapsigargin. Images provided by GM Findlay. (B) STIM1 and ORAI1 at an ER-plasma membrane junction. This schematic view conveys the arrangement and relative dimensions of STIM1, ORAI1, and the apposed membranes that define the junction. The detailed structure and stoichiometry of the active STIM-ORAI complex have not been determined.
FIGURE 2
FIGURE 2
(A) Idealized STIM-ORAI microdomain. The compartment delimited by the apposed membranes is taken as 15 nm in depth and 150 nm in outer radius. For convenience in calculation, a single ORAI channel is placed at the center of the idealized microdomain, though placing the channel elsewhere in the microdomain would not alter the qualitative conclusions. The region less than 10 nm from the mouth of the channel is not included in the model for reasons noted in the text. (B) Steady-state concentration profile. The increment in Ca2+ concentration over the Ca2+ concentration at the outer boundary of the microdomain is plotted against radial distance r from the mouth of the channel. Small concentration differences across the depth of the microdomain that may exist near its inner boundary are not considered. Other caveats are stated in the text. The increment in Ca2+ concentration at radial distance r, obtained as the steady-state solution of the diffusion equation under the stated conditions, is K(Φ∕2πDz)ln(R0∕r), where the flux of Ca2+ Φ = 6300 ions/s, the diffusion coefficient for Ca2+ D = 220 μm2/s, the depth of the annulus z = 15 nm, and the outer radius of the annulus R0 = 150 nm. K = 1.66 × 10−9 is the factor required to convert the units from ions/μm3 to M.
FIGURE 3
FIGURE 3
Free diffusion of Ca2+ is rapid. The probability density for finding an individual Ca2+ ion is plotted against radial distance r for times t = 1 μs, 10 μs, 100 μs, and 1 ms, assuming that the Ca2+ ion emerges from a channel at the central location r = 0 at t = 0. Formally, the variable plotted is ∂P/∂r, where P(r,t) is the probability that Ca2+ is found at a radial distance less than r at time t. Its value, which can derived from the diffusion equation, is (r∕2Dt)exp(−r2∕4Dt). The model used in this case differs slightly from that in Figure 2A, in that the model compartment extends to infinity and the region near the channel is not excluded. Note that this example of free diffusion is shown as an explicit counterpoint to the situation in cells, where binding sites and transporters will detain or contain Ca2+.
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