IP3 Receptors: Toward Understanding Their Activation

Abstract

Inositol 1,4,5-trisphosphate receptors (IP 3 R) and their relatives, ryanodine receptors, are the channels that most often mediate Ca 2þ release from intracellular stores.Their regulation by Ca 2þ allows them also to propagate cytosolic Ca 2þ signals regeneratively.This brief review addresses the structural basis of IP 3 R activation by IP 3 and Ca 2þ .IP 3 initiates IP 3 R activation by promoting Ca 2þ binding to a stimulatory Ca 2þ -binding site, the identity of which is unresolved.We suggest that interactions of critical phosphate groups in IP 3 with opposite sides of the clam-like IP 3 -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 IP 3 R 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 IP 3 R.A BRIEF HISTORY OF IP 3 RECEPTORS S idney Ringer, in his famous correction to an earlier paper, showed that Ca 2þ entry can evoke a physiological response by demonstrating that beating of the frog heart requires extracellular Ca 2þ (Ringer 1883).Almost a century passed before it became clear that this Ca 2þ entry, via voltage-gated Ca 2þ channels, was not directly responsible for contraction, but instead provided the trigger for a much larger release of Ca 2þ from stores within the sarcoplasmic reticulum (SR).The latter is mediated by type-2 ryanodine receptors (RyR) (Fabiato 1983;Cheng et al. 1993), which like many Ca 2þ channels, are ablebothtotransportCa 2þ throughanopenpore and respond to it.These observations highlight two general points.First, cells call upon two sources of Ca 2þ to evoke increases in cytosolic Ca 2þ concentration; second, interactions between these Ca 2þ fluxes across the plasma membrane and the membranes of intracellular stores are important determinants of the physiological response.The same points apply to the Ca 2þ signals evoked by receptors that stimulate phospholipase C (PLC) and, thereby, formation of inositol 1,4,5-trisphosphate (IP 3 ).The biochemical sequence linking these receptors to formation of IP 3 emerged in the 1980s (Michell et al. 1989;Berridge 2005), but work in the decade before had established that many receptors regulate many different responses by increasing the cytosolic Ca 2þ concentration (Rasmussen 1970;Berridge 1975).