IP₃ Receptors: Toward Understanding Their Activation

Abstract

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.