Forms and functions of store-operated calcium entry mediators, STIM and Orai

Abstract

Calcium signals arise by multiple mechanisms, including mechanisms of release of intracellular stored Ca²⁺, and the influx of Ca²⁺ through channels in the plasma membrane. One mechanism that links these two sources of Ca²⁺ is store-operated Ca²⁺ entry, the most commonly encountered version of which involves the extensively studied calcium-release-activated Ca²⁺ (CRAC) channel. The minimal and essential molecular components of the CRAC channel are the STIM proteins that function as Ca²⁺ sensors in the endoplasmic reticulum, and the Orai proteins that comprise the pore forming subunits of the CRAC channel. CRAC channels are known to play significant roles in a wide variety of physiological functions. This review discusses the multiple forms of STIM and Orai proteins encountered in mammalian cells, and discusses some specific examples of how these proteins modulate or mediate important physiological processes.

Figure 1. N-terminal sequence of Orai1

Two methionines in the N-terminus can serve as initiation sites, at position 1 and position 64, resulting in two forms of Orai1. Potential sequences in the longer version include a caveolin binding site (Yu et al., 2010), an adenylyl cyclase 8 binding site (Willoughby et al., 2012), a potential phosphatidylinositol 4,5-bisphosphate binding site, two potential protein kinase C phosphorylation sites (Kawasaki et al., 2010), and a recognition site for the membrane skeletal protein 4.1 (GASCARD et al., 1993).

Figure 2. Actions of the key SOCE mediators, STIM1 and Orai1

Signaling is generally initiated by agonist (Ag) acting through a receptor (R) and G-protein (G) to activate phospholipase C (PLC) and produce the Ca²⁺-mobilizing messenger, inositol 1,4,5-trisphosphate (IP₃). IP₃ in turn activates the IP₃ receptor (IP3R) in the endoplasmic reticulum. The fall in Ca²⁺ in the endoplasmic reticulum activates STIM1 to aggregate and migrate to specific sites near the plasma membrane where Orai1 channels are activated resulting in SOCE. Channels composed of Orai1 and Orai3 (not shown) subunits can also be activated in a non-store-operated mode by arachidonic acid or a metabolite, leukotriene C4. Calcium entering through Orai1 channels can recruit and together with STIM1 activated certain members of the TRPC cation channel family. Some members of the TRPC cation family can also be activated more directly by products of phospholipase C. Calcium entering the cytoplasm through all of these routes regulates and activates a myriad of cell responses, some of which were discussed in the current review.