The inositol trisphosphate calcium channel is inactivated by inositol trisphosphate

ACTIVATION of intracellular Ca²⁺ channels by inositol 1,4,5-tris-phosphate (Ins(l,4,5)P₃) represents the initial Ca ²⁺ mobilization step in response to many extracellular signals ¹. Here we report that Ins(l,4,5)P₃-induced channel activation in permeabilized hepatocytes is followed by a time-dependent inactivation, which is a direct consequence of ligand binding. The inactivation by Ins(l,4,5)P₃ parallels the quantal character of channel opening, giving rise to a unique process of incremental inactivation whereby discrete channel populations are inhibited at each Ins(l,4,5)P₃ dose. Ins(l,4,5)P₃ can induce inactivation in the absence of stored Ca ²⁺, but the inactivation rate is enhanced by increases of cytosolic Ca²⁺. The inhibitory effect of Ins(l,4,5)P₃ can be reversed by Ins(l,4,5)P₃ washout, or by chelation of cytosolic Ca²⁺. Thus, Ins(l,4,5)P₃ and Ca²⁺ act as coinhibitors of the Ins(l,4,5)P₃-sensitive Ca²⁺ channel. Inactivation is an inherent consequence of Ins(l,4,5)P₃-induced channel opening which can terminate increases of cytosolic Ca²⁺.