The enhanced metabolism of phosphoinositides, which is associated with a wide variety of stimuli and physiological responses, has been studied intensively. Berridge and his collaborators demonstrated that the first measurable reaction following cell membrane receptor activation is a rapid hydrolysis of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2), and that the product of this reaction, inositol 1,4,5-trisphosphate (Ins(1,4,5)P3), could cause a release of non-mitochondrial calcium. These findings have been verified in other systems. Although the relationship between the hydrolysis of PtdIns(4,5)P2 and the mobilization of intracellular calcium was clearly demonstrated, the direct link between Ins(1,4,5)P3 production and the physiological response was only implied. We have investigated the possibility that the intracellular release of Ins(1,4,5)P3 mediates the muscarinic-cholinergic response is Xenopus oocytes, and we show here that intracellularly injected Ins(1,4,5)P3 mimics the muscarinic depolarizing chloride current in Xenopus oocytes. This is the first demonstration of a direct link between phosphoinositides metabolism and a neuro-transmitter-induced physiological response.