The effect of neurotensin on intracellular calcium mobilization was measured in PC12 cells transfected with the cDNA sequence encoding the rat neurotensin receptor. Stimulation with nanomolar concentrations of neurotensin induced a rapid increase of the [Ca++]i. This response was transient and the [Ca++]i returned to basal level within 2 minutes, despite the continuous presence of the agonist. The response was also observed in the absence of extracellular calcium, indicating the intracellular origin of the released calcium. Successive stimulations with the same concentration of the peptide failed to produce similar responses. ATP was also found to mediate the release from the same intracellular store of calcium in PC12 cells. The amplitude of the response to ATP was not affected by previous stimulation with neurotensin. These results demonstrate the existence of a rapid and homologous desensitization of the neurotensin-induced calcium release in PC12 transfected cells.