Neuropeptide Y (NPY) is far more abundant in the dentate gyrus than elsewhere in the hippocampal formation, but it does not alter the synaptic excitation of dentate granule cells (DGCs) as it does for pyramidal cells in areas CA1 and CA3. NPY inhibited depolarization-induced increases in intracellular Ca2+ concentrations ([Ca2+]i) in DGCs in hippocampal slices, without altering the resting [Ca2+]i. NPY inhibited Ca2+ currents (ICa) via a Y1 receptor in 84% of acutely isolated DGCs and via a Y2 receptor in 31% of the NPY-responsive cells tested. ICa inhibition was completely occluded by omega-conotoxin-GVIA but not by nimodipine. The inhibition of ICa was accompanied by a change in the time course of ICa activation in only 27% of NPY-responsive cells. Only 23% of DGCs responded to NPY when Ba2+ was substituted for extracellular Ca2+ and when [Ca2+]i was strongly buffered. Therefore, NPY inhibits an N-type ICa in DGCs, mainly via Y1 receptors. Furthermore, it seems that more than one mechanism, one of which may be sensitive to [Ca2+]i, may couple NPY receptors to the Ca2+ channels in DGCs. Because the release of dynorphin from DGCs depends in part on N-type currents, NPY receptors are poised to regulate the release of opioid peptides from DGC somata and dendrites.