Assembly of ER-PM Junctions: A Critical Determinant in the Regulation of SOCE and TRPC1

Abstract

Store-operated calcium entry (SOCE), a unique plasma membrane Ca²⁺ entry mechanism, is activated when ER-[Ca²⁺] is decreased. SOCE is mediated via the primary channel, Orai1, as well as others such as TRPC1. STIM1 and STIM2 are ER-Ca²⁺ sensor proteins that regulate Orai1 and TRPC1. SOCE requires assembly of STIM proteins with the plasma membrane channels which occurs within distinct regions in the cell that have been termed as endoplasmic reticulum (ER)-plasma membrane (PM) junctions. The PM and ER are in close proximity to each other within this region, which allows STIM1 in the ER to interact with and activate either Orai1 or TRPC1 in the plasma membrane. Activation and regulation of SOCE involves dynamic assembly of various components that are involved in mediating Ca²⁺ entry as well as those that determine the formation and stabilization of the junctions. These components include proteins in the cytosol, ER and PM, as well as lipids in the PM. Recent studies have also suggested that SOCE and its components are compartmentalized within ER-PM junctions and that this process might require remodeling of the plasma membrane lipids and reorganization of structural and scaffolding proteins. Such compartmentalization leads to the generation of spatially- and temporally-controlled Ca²⁺signals that are critical for regulating many downstream cellular functions.

Keywords: ER-PM junctions; Orai1; SOCE; STIM1; STIM2; TRPC1.