Substance P enhances NMDA channel function in hippocampal dentate gyrus granule cells.
Substance P (SP)-containing afferents and the NK-1 tachykinin receptor to which SP binds are present in the dentate gyrus of the rat; however, direct actions of SP on principal cells have not been demonstrated in this brain region. We have examined the effect of SP on N-methyl--aspartate (NMDA) channels from acutely isolated dentate gyrus granule cells of adult rat hippocampus to assess the ability of SP to regulate glutamatergic input. SP produces a robust enhancement of single NMDA channel function that is mimicked by the NK-1-selective agonist Sar9, Met(O2)11-SP. The SP-induced prolongation of NMDA channel openings is prevented by the selective NK-1 receptor antagonist (+)-(2S, 3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994). Calcium influx or activation of protein kinase C were not required for the SP-induced increase in NMDA channel open durations. The dramatic enhancement of excitatory amino acid-mediated excitability by SP places this neuropeptide in a key position to gate activation of hippocampal network activity.
Lieberman
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DN
Neuroscience Graduate Program, Stanford University School of Medicine, Stanford 94305, USA.
Mody
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D000818:Animals; D002478:Cells, Cultured; D018891:Dentate Gyrus / Q000502:physiology*; D015640:Ion Channel Gating / Q000187:drug effects; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology*; D018040:Receptors, Neurokinin-1 / Q000819:agonists / Q000502:physiology; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology*
D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D018040:Receptors, Neurokinin-1; C062618:substance P, Sar(9)-Met(O2)(11)-; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine; D013373:Substance P