STIM Proteins and Regulation of SOCE in ER-PM Junctions

Abstract

ER-PM junctions are membrane contact sites formed by the endoplasmic reticulum (ER) and plasma membrane (PM) in close apposition together. The formation and stability of these junctions are dependent on constitutive and dynamic enrichment of proteins, which either contribute to junctional stability or modulate the lipid levels of both ER and plasma membranes. The ER-PM junctions have come under much scrutiny recently as they serve as hubs for assembling the Ca²⁺ signaling complexes. This review summarizes: (1) key findings that underlie the abilities of STIM proteins to accumulate in ER-PM junctions; (2) the modulation of Orai/STIM complexes by other components found within the same junction; and (3) how Orai1 channel activation is coordinated and coupled with downstream signaling pathways.

Keywords: ER-PM junctions; Orai1; SOCE; STIM; calcium signaling; phospholipids.

Figure 1

Cytoskeletal remodeling in ER-PM junctions. Remodeling of the actin cytoskeleton and septin filaments to enable formation and stabilization of ER-PM junctions populated by STIM1/Orai1 signaling complex [38].

Figure 2

Functional communication between IP₃R and STIM2 at subthreshold stimuli is a critical checkpoint for initiation of SOCE. The model refers to cellular responses under ambient and low-intensity stimuli. IP₃R and STIM2 are localized in the ER–PM junctional region. Under ambient conditions (without agonist addition), constitutive PLC-dependent PIP₂ hydrolysis as well as cAMP/PKA activity regulate IP₃R activity. When STIM2 is in the vicinity of a functional IP₃R, it senses the lower [Ca²⁺]_ER (1), which leads to scaffolding to the plasma membrane and immobilization (2). Orai1 is then recruited to immobile STIM2 (3) and with further [Ca²⁺]_ER decrease STIM1 is also recruited to immobile STIM2 (4) [5].