IP3 receptors a nd their regulation by calmodulin and cytosolic Ca2+

Inositol 1,4,5-trisphosphate (IP3) receptors are tetrameric intracellular Ca2+ channels, the opening of which is regulated by both IP3 and Ca2+. We suggest that all IP3 receptors are biphasically regulated by cytosolic Ca2+, which binds to two distinct sites. IP3 promotes channel opening by controlling whether Ca2+ 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 IP3 receptors by Ca2+ 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 IP3 receptor, while the other lobe can bind Ca2+ and then interact with a second site on the receptor to cause inhibition. (C) 2002 Elsevier Science Ltd. All rights reserved.