Fig 1: Dual regulation of SOCE by IP3Rs.(A) SOCE is activated when loss of Ca2+ from the ER, usually mediated by opening of IP3Rs when they bind IP3, causes STIM to unfurl cytosolic domains (2). The exposed cytosolic domains of STIM1 reach across a narrow gap between the ER and PM at a MCS to interact with PIP2 and Orai1 in the PM. Binding of STIM1 to Orai1 causes pore opening, and SOCE then occurs through the open Orai1 channel. We show that IP3Rs when they bind IP3 also facilitate interactions between Orai1 and STIM, perhaps by stabilizing the MCS (1). Receptors that stimulate IP3 formation thereby promote both activation of STIM (by emptying Ca2+ stores) and independently promote interaction of active STIM1 with Orai1. (B) Other mechanisms, including ryanodine receptors (RyR), can also release Ca2+ from the ER. We suggest that convergent regulation of SOCE by IP3R with bound IP3 allows receptors that stimulate IP3 formation to selectively control SOCE.