Significance IP 3 receptors are well-documented regulators of intracellular calcium concentration, but their role in axons of central neurons remains unexplored. Here we show that IP 3 receptors are present throughout the axon of cerebellar Purkinje cells where their activation leads to calcium release from intracellular stores. We reveal distinct, sharply delimited signaling cascades leading to IP 3 production in the axon initial segment (AIS), in the more distal part of the axon, and in synaptic terminals. In the AIS, IP 3 -induced calcium rises inhibit action potential generation, whereas similar signals in axonal terminals increase transmitter release. Metabotropic purinergic receptors appear to control the IP 3 -driven cascade. Altogether, the results reveal potent actions of IP 3 in central axons, which are both diverse and spatially constrained.