IP3 Receptors: Toward Understanding Their Activation

Inositol 1,4,5-trisphosphate receptors (IP3R) and their relatives, ryanodine receptors, are the channels that most often mediate Ca2+ release from intracellular stores. Their regulation by Ca2+ allows them also to propagate cytosolic Ca2+ signals regeneratively. This brief review addresses the structural basis of IP3R activation by IP3 and Ca2+. IP3 initiates IP3R activation by promoting Ca2+ binding to a stimulatory Ca2+-binding site, the identity of which is unresolved. We suggest that interactions of critical phosphate groups in IP3 with opposite sides of the clam-like IP3-binding core cause it to close and propagate a conformational change toward the pore via the adjacent N-terminal suppressor domain. The pore, assembled from the last pair of transmembrane domains and the intervening pore loop from each of the four IP3R subunits, forms a structure in which a luminal selectivity filter and a gate at the cytosolic end of the pore control cation fluxes through the IP3R.