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Fig. 1. Proposed mechanisms for signaling capacitative calcium entry. In all models, agonist activation results in the production of Ins(1,4,5)P3, which results in discharge of stored Ca2+. Alternatively, Ca2+ stores can be discharged passively through the use of reagents such as thapsigargin or ionomycin (not shown). (A) Following discharge of the stores, a diffusible signal – Ca2+-influx factor (CIF) – is released from the ER and activates plasma membrane store-operated channels. (B) In the exocytosis model, depletion of stores (in this depiction, through something similar to the conformational coupling model) causes fusion of vesicles containing CRAC channels with the plasma membrane. (C) In the Ca2+ regulation model, Ca2+ discharged from a replete Ca2+ pool keeps the channels in an inhibited state. Discharge of the stores removes the source of this inhibitory Ca2+ and relieves the inhibition. (D) In the conformational coupling model, discharge of Ca2+ stores leads to a conformational change in the Ins(1,4,5)P3 receptor, which is transmitted to plasma membrane Ca2+ channels by a direct protein-protein interaction. Abbreviations: R, agonist receptor; Ag, agonist; G, heterotrimeric G protein; PLC, polyphosphoinositide phospholipase C; CRAC, Ca2+ release-activated Ca2+ (channel); ER, endoplasmic reticulum; Ins(1,4,5)P3, inositol 1,4,5-trisphosphate; Ins(1,4,5)P3R, Ins(1,4,5)P3 receptor; CIF, Ca2+-influx factor; SP, scaffolding protein.
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