The distributions of inositol 1,4,5-trisphosphate and ryanodine receptors (InsP3R and RyR) and the patterns of increase in intracellular calcium ion concentration ([Ca2+]i) elicited by their activation were compared in cultured hippocampal neurons. InsP3R and RyR were labeled using specific antibodies and formed small aggregations in the somata and dendrites of pyramidally shaped neurons. Both receptors were densest in somata. In dendrites the InsP3R and RyR were not distributed homogeneously; InsP3R was found in all regions, while RyR was least dense in fine processes. Increases in [Ca2+]i elicited by acetylcholine (to activate InsP3 receptors via muscarinic receptors) and caffeine (to stimulate ryanodine receptors) were measured in dendrites using Ca(2+)-sensitive fluorescent dyes and confocal microscopy. Ca2+ responses to acetylcholine were transient and observed in proximal and distal dendritic regions. In contrast, caffeine-induced responses were sustained and restricted to proximal dendrites. Thus the patterns of calcium release in fine dendrites mirrored the distributions of InsP3R and RyR. Calcium responses to both acetylcholine and caffeine were observed in the absence of external calcium and thus were dependent on Ca2+ release. Ca2+ responses showed localized fluctuations and variations in response delay times. Sequential activation of InsP3R and RyR in somata resulted in mutual occlusion of Ca2+ release. The existence of InsP3-gated and Ca(2+)- induced Ca2+ release as spatially distinct, but mutually interacting, mechanisms may be important in the generation of oscillations and propagating Ca2+ waves in somata and dendrites of hippocampal neurons.