Inositol 1,4,5-trisphosphate (IP(3)) receptors are tetrameric intracellular Ca(2+) channels, the opening of which is regulated by both IP(3) and Ca(2+). We suggest that all IP(3) receptors are biphasically regulated by cytosolic Ca(2+), which binds to two distinct sites. IP(3) promotes channel opening by controlling whether Ca(2+) binds to the stimulatory or inhibitory sites. The stimulatory site is probably an integral part of the receptor lying just upstream of the pore region. Inhibition of IP(3) receptors by Ca(2+) probably requires an accessory protein, which has not yet been unequivocally identified, but calmodulin is a prime candidate. We speculate that one lobe of calmodulin tethers it to the IP(3) receptor, while the other lobe can bind Ca(2+) and then interact with a second site on the receptor to cause inhibition.
