Regulation of store-operated Ca2+ entry by IP3 receptors independent of their ability to release Ca2+

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 .