The inositol 1,4,5-trisphosphate receptor (InsP(3)R) is the mai(n) calcium(Ca2+) release channel in most tissues. Three isoforms have been identified(1-6), but only types I and II InsP(3)R have been characterized(7,8). Here we examine the functional properties of the type In InsP(3)R because this receptor is restricted to the trigger zone from which Ca2+ waves originate(9-11) and it has distinctive InsP(3)-binding properties(12,13). We find that type III InsP(3)R forms Ca2+ channels with single-channel currents that are similar to those of type I InsP(3)R; however, the open probability of type III InsP(3)R isoform increases monotonically with increased cytoplasmic Ca2+ concentration, whereas the type I isoform has a bell-shaped dependence on cytoplasmic Ca2+. The properties of type III InsP(3)R provide positive feedback as Ca2+ is released; the lack of negative feedback allows complete Ca2+ release from intracellular stores. Thus, activation of type III InsP(3)R in cells that express only this isoform results in a single transient, but global, increase in the concentration of cytosolic Ca2+. The bell-shaped Ca2+-dependence awe of type I InsP(3)R is ideal for supporting Ca2+ oscillations, whereas the properties of type III InsP(3)R are better suited to signal initiation.