Ryanodine receptor-2: a necessity for gating store-operated Ca2+ channels.

Abstract

This editorial refers to ‘Conformation of ryanodine receptor-2 gates store-operated calcium entry in rat pulmonary arterial myocytes’ by A.H.Y. Lin et al ., pp. 94–104. Store-operated Ca2+ entry (SOCE) is an important regulator of vascular tone as it is linked to a variety of functions including contraction, proliferation, and migration.1,2 It is well established that plasma membrane store-operated Ca2+ channel (SOCs) activation induces SOCE. Stimulation of surface receptors G protein and tyrosine kinase by extracellular agonists activates the phospholipase C (PLC)/phosphatidylinositol 4,5-bisphosphate (PIP2)/inositol 1,4,5-triphosphate (IP3) pathway that leads to IP3-mediated depletion of endoplasmic/sarcoplasmic reticulum (ER/SR) Ca2+ stores and subsequent activation of SOCs. Stromal interaction molecule (STIM1-2) and Orai (Orai1-3) proteins are identified as critical components in SOCs activation. Of these proteins, structure models for STIM1 and Orai have begun to illustrate the molecular mechanisms controlling activation of SOCs in many cell types including vascular smooth muscle cells (VSMCs).3–5 It has been shown that SOCE is driven by physical contact between STIM1 and Orai1 through the cytosolic CAD domain of STIM1, which binds directly to Orai1 inducing tetrameric channel formation in ER–PM junction.6 Members of the canonical transient receptor potential family (TRPC) have also been proposed to act as SOCs; in particular, TRPC1 is associated with SOCE in VSMCs.7,8 Similar to Orai1, STIM1 is also needed for TRPC1 channel formation in response to ER/SR Ca2+ store depletion. It has been suggested, however, that STIM1-dependent gating of TRPC1 is different from Orai1. Instead of binding directly, an electrostatic model proposed that gating is mediated by an intermolecular electrostatic …