Regulation of store-operated Ca entry by IP receptors independent of their ability to release Ca.

Loss of endoplasmic reticular (ER) Ca activates store-operated Ca entry (SOCE) by causing the ER localized Ca sensor STIM to unfurl domains that activate Orai channels in the plasma membrane at membrane contact sites (MCS). Here, we demonstrate a novel mechanism by which the inositol 1,4,5 trisphosphate receptor (IPR), an ER-localized IP-gated Ca channel, regulates neuronal SOCE. In human neurons, SOCE evoked by pharmacological depletion of ER-Ca is attenuated by loss of IPRs, and restored by expression of IPRs even when they cannot release Ca, but only if the IPRs can bind IP. Imaging studies demonstrate that IPRs enhance association of STIM1 with Orai1 in neuronal cells with empty stores; this requires an IP-binding site, but not a pore. Convergent regulation by IPRs, may tune neuronal SOCE to respond selectively to receptors that generate IP.