New molecular players in capacitative Ca2+ entry

Abstract

Capacitative Ca2+ entry links the emptying of intracellular Ca2+ stores to the activation of store-operated Ca2+ channels in the plasma membrane. In the twenty years since the inception of the concept of capacitative Ca2+ entry, a number of activation mechanisms have been proposed, and there has been considerable interest in the possibility that TRP channels function as store-operated channels. However, in the past two years, two major players in both the signaling and permeation mechanisms for store-operated channels have been discovered: Stim1 and the Orai proteins. Stim1 is an endoplasmic reticulum Ca2+ sensor. It appears to act by redistributing within a small component of the endoplasmic reticulum, approaching the plasma membrane, but does not seem to translocate into the plasma membrane. Stim1 signals to plasma membrane Orai proteins, which constitute pore-forming subunits of store-operated channels.

Figure 1. Current understanding of the roles of Stim1 and Orai

Agonist (Ag) activation of a plasma membrane receptor (R) results in formation of IP₃, which activates the IP₃ receptor (IP3R) causing discharge of stored 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 Ca²⁺ dissociation from Stim1, which causes Stim1 to redistribute within the endoplasmic reticulum to areas near Orai channels that reside in the plasma membrane. Stim1 then activates Ca²⁺-selective Orai channels; the mechanism by which this activation is accomplished is unknown at present. Stim1 is also present in the plasma membrane, although its function there is unclear. TRPC channels can also be activated by phospholipase C (PLC) –dependent mechanisms. There is evidence that in some instances, perhaps when combined with other subunits, they can function as store-operated channels, perhaps also involving Stim1 as an activator.