Orai, STIM1 and iPLA2beta: a view from a different perspective

Abstract

The mechanism of store-operated Ca(2+) entry (SOCE) remains one of the intriguing mysteries in the field of Ca(2+) signalling. Recent discoveries have resulted in the molecular identification of STIM1 as a Ca(2+) sensor in endoplasmic reticulum, Orai1 (CRACM1) as a plasma membrane channel that is activated by the store-operated pathway, and iPLA(2)beta as an essential component of signal transduction from the stores to the plasma membrane channels. Numerous studies have confirmed that molecular knock-down of any one of these three molecules impair SOCE in a wide variety of cell types, but their mutual relations are far from being understood. This report will focus on the functional roles of Orai1, STIM1 and iPLA(2)beta, and will address some specific questions about Orai1 and TRPC1, and their relation to SOC channels in excitable and non-excitable cells. Also, it will analyse the novel role of STIM1 as a trigger for CIF production, and the complex relationship between STIM1 and Orai1 expression, puncta formation and SOCE activation. It will highlight some of the most recent findings that may challenge simple conformational coupling models of SOCE, and will offer some new perspectives on the complex relationships between Orai1, STIM1 and iPLA(2)beta in the SOCE pathway.

Figure 1. Two Ca²⁺ entry pathways can be mediated by two distinct channels, Orai1-dependent SOC and TRPC1-dependent IP₃ROC

Both pathways may be activated upon receptor (R) and G-protein (G)-mediated stimulation of phospholipase C (PLC) that leads to IP₃ production. The store-operated pathway (on the right) is activated upon depletion of Ca²⁺ stores, which leads to oligomerization and accumulation of STIM1 in ER membrane in close proximity to plasma membrane. STIM1 triggers production of calcium influx factor (CIF) that displaces inhibitory calmodulin (CaM) from a plasma membrane bound Ca²⁺-independent phospholipase A₂ (iPLA₂β), which produces lysophospholipids and activates Orai1-dependent SOC channels that are responsible for the store-operated Ca²⁺ entry (SOCE). The IP₃ receptor-operated pathway (on the left) does not require store depletion, and is activated by IP₃-dependent conformational coupling of IP₃ receptor (IP₃R) and TRPC1-encoded plasma membrane channel (IP₃ROC). From Zarayskiy et al. 2007, ©Landes Bioscience.