title: Role of neurokinin 3 receptors in supraoptic vasopressin and oxytocin neurons.
abstract: Neurokinin 3 receptors (NK3-Rs) are expressed in the supraoptic nucleus (SON), and SON is innervated by substance P (SP)-expressing A1 neurons in the medulla. Because SP stimulates vasopressin (VP) and oxytocin release from explants of the hypothalamo-neurohypophyseal system (HNS), two hypotheses were tested: (1) SP-stimulated VP release is mediated by NK3-Rs, and (2) stimulation of the A1 pathway by hypotension activates SON NK3-Rs. Senktide, an NK3-R agonist, stimulated VP release from HNS explants, but neither a neurokinin 1 receptor antagonist [L732,138 (N-acetyl-L-tryptophan 3,5-bis(tri-fluoromethyl)benzyl ester)] nor two NK3-R antagonists (SB222200 and SB235375) prevented SP-stimulated VP release. Because the affinity of these antagonists for rat NK-Rs may limit their efficacy, NK3-R internalization was used to assess the ability of SP to activate SON NK3-Rs. Senktide, SP, or vehicle was microinjected above SON. The brain was perfused 5 min after injection and stained for NK3-R immunoreactivity. Using confocal microscopy, the number of NK3-R-immunoreactive (-IR) endosomes was counted in a 5.6(2) mu region of cytoplasm in SON neurons. Senktide, but not SP or vehicle, significantly increased the number of NK3-R-IR endosomes in the cytoplasm. When hypotension was induced with hydralazine, NK3-R internalization was observed within 5 min (p < 0.005). A decrease in cytoplasmic NK3-R immunoreactivity was observed within 15 min of hypotension. Unexpectedly, both senktide and hypotension resulted in translocation of NK3-R-IR immunoreactivity to the nucleus. Thus, although these studies do not identify SP as the NK3-R ligand, they do provide evidence for hypotension-induced release of an endogenous tachykinin in SON and evidence suggesting a role for NK3-Rs in transcription regulation.
authors.affiliation: Department of Physiology and Biophysics, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
authors.forename: Heather E
authors.initials: HE
authors.lastname: Howe
authors.forename: Suwit J
authors.initials: SJ
authors.lastname: Somponpun
authors.forename: Celia D
authors.initials: CD
authors.lastname: Sladek
mesh_terms: D000085:Acetates / Q000494:pharmacology; D000818:Animals; D002395:Catecholamines / Q000502:physiology; D002451:Cell Compartmentation; D002467:Cell Nucleus / Q000737:chemistry; D003593:Cytoplasm / Q000737:chemistry; D011992:Endosomes / Q000737:chemistry; D006830:Hydralazine / Q000494:pharmacology; D007022:Hypotension / Q000139:chemically induced / Q000503:physiopathology*; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology*; D007032:Hypothalamus, Anterior / Q000378:metabolism*; D008297:Male; D008845:Microinjections; D018613:Microscopy, Confocal; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D010121:Oxytocin / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects / Q000502:physiology; D018040:Receptors, Neurokinin-1 / Q000187:drug effects / Q000502:physiology; D018042:Receptors, Neurokinin-3 / Q000187:drug effects / Q000502:physiology*; D013373:Substance P / Q000031:analogs & derivatives* / Q000494:pharmacology; D015320:Tachykinins / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000494:pharmacology; D014667:Vasopressins / Q000378:metabolism*
chemical_list: D000085:Acetates; D002395:Catecholamines; C444647:N-(alpha-ethylbenzyl)-3-(carboxymethoxy)-2-phenylquinoline-4-carboxamide; D010446:Peptide Fragments; D011804:Quinolines; D043562:Receptors, G-Protein-Coupled; D018040:Receptors, Neurokinin-1; D018042:Receptors, Neurokinin-3; C109112:SB 222200; D015320:Tachykinins; C054724:senktide; D014667:Vasopressins; C086089:3,5-bis(trifluoromethyl)benzyl N-acetyltryptophan; D006830:Hydralazine; D013373:Substance P; D010121:Oxytocin; D014364:Tryptophan