Recent breakthroughs in the molecular mechanism of capacitative calcium entry (with thoughts on how we got here) - PubMed (original) (raw)

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Recent breakthroughs in the molecular mechanism of capacitative calcium entry (with thoughts on how we got here)

James W Putney Jr. Cell Calcium. 2007 Aug.

Abstract

Activation of phospholipase C by G-protein-coupled receptors results in release of intracellular Ca(2+) and activation of Ca(2+) channels in the plasma membrane. The intracellular release of Ca(2+) is signaled by the second messenger, inositol 1,4,5-trisphosphate. Ca(2+) entry involves signaling from depleted intracellular stores to plasma membrane Ca(2+) channels, a process referred to as capacitative calcium entry or store-operated calcium entry. The electrophysiological current associated with capacitative calcium entry is the calcium-release-activated calcium current, or I(crac). In the 20 years since the inception of the concept of capacitative calcium entry, a variety of activation mechanisms have been proposed, and there has been considerable interest in the possibility of transient receptor potential channels functioning as store-operated channels. However, in the past 2 years, two major players in both the signaling and permeation mechanisms for store-operated channels have been discovered: Stim1 (and possibly Stim2) and the Orai proteins. Activation of store-operated channels involves an endoplasmic reticulum Ca(2+) sensor called Stim1. Stim1 acts by redistributing within a small component of the endoplasmic reticulum, approaching the plasma membrane, but does not appear to translocate into the plasma membrane. Stim1, either directly or indirectly, signals to plasma membrane Orai proteins which constitute pore-forming subunits of store-operated channels.

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Figures

Figure 1

Figure 1. Primitive version of capacitative calcium entry

The intracellular Ca2+ store was envisioned as bound to the plasma membrane, occluding the Ca2+ channel. release of the bound Ca2+ was associated with gating of the Ca2+ channel. Redrawn from [3] with permission.

Figure 2

Figure 2. Stim1 rearranges following Ca2+ store depletion, but the endoplasmic reticulum does not

A and B: Thapsigargin causes rearrangement of YFP-Stim1 from a fibrillar or tubular arrangement into punctae. From [49] with permission. C and D: Endoplasmic reticulum-targeted GFP does not redistribute or rearrange following Ca2+ store depletion. From [53] with permission.

Figure 3

Figure 3. Current understanding of the roles of Stim1 and Orais

Agonist activation of a plasma membrane receptor (R) results in formation of IP3, which activates the IP3 receptor (IP3R) causing discharge of store Ca2+ from a subcompartment of the endoplasmic reticulum. Within this subcompartment, Ca2+ binds reversibly to an EF hand motif in Stim1; depletion of Ca2+ results in Stim1 without Ca2+ bound, which causes Stim1 to redistribute within the endoplasmic reticulum to areas near Orai within the plasma membrane. Stim1 then activates Ca2+-selective Orai channels; the mechanism whereby this activation is accomplished is unknown. Stim1 is also present in the plasma membrane, although its function there is unclear.

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