Regulation of store-operated Ca(2+) entry by IP(3) receptors independent of their ability to release Ca(2+)

Loss of endoplasmic reticular (ER) Ca(2+) activates store-operated Ca(2+) entry (SOCE) by causing the ER localized Ca(2+) 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 (IP(3)R), an ER-localized IP(3)-gated Ca(2+) channel, regulates neuronal SOCE. In human neurons, SOCE evoked by pharmacological depletion of ER-Ca(2+) is attenuated by loss of IP(3)Rs, and restored by expression of IP(3)Rs even when they cannot release Ca(2+), but only if the IP(3)Rs can bind IP(3). Imaging studies demonstrate that IP(3)Rs enhance association of STIM1 with Orai1 in neuronal cells with empty stores; this requires an IP(3)-binding site, but not a pore. Convergent regulation by IP(3)Rs, may tune neuronal SOCE to respond selectively to receptors that generate IP(3).