Abstract
Loss of ER Ca2+ activates store-operated Ca2+ entry (SOCE) by causing STIM1 to unfurl domains that activate Orai1 channels in the plasma membrane at membrane contact sites (MCS). In human neurons, SOCE evoked by thapsigargin to deplete ER Ca2+ is attenuated by loss of IP3Rs, and restored by expression of IP3Rs even when they cannot releaseCa2+, but only if they can bind IP3. In cells expressing pore-dead IP3Rs, IP3 enhances SOCE evoked by partial store depletion without enhancing Ca2+ release. Proximity ligation assays establish that IP3Rs enhance association of STIM1 with Orai1 in cells with empty stores; this requires an IP3-binding site, but not a pore. Over-expressing STIM1, or extended synaptotagmin-1 to exaggerate MCS, circumvents the need for IP3Rs. Thus, IP3 binding to IP3Rs stimulates SOCE by both mediating ER Ca2+ release and promoting STIM1-Orai1 interactions. Convergent regulation by IP3Rs may tune SOCE to respond selectively to IP3.
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