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The Journal of Neuroscience, November 10, 2004, 24(45):10103-10110; doi:10.1523/JNEUROSCI.3164-04.2004

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Behavioral/Systems/Cognitive
Role of Neurokinin 3 Receptors in Supraoptic Vasopressin and Oxytocin Neurons

Heather E. Howe, Suwit J. Somponpun, and Celia D. Sladek

Department of Physiology and Biophysics, University of Colorado Health Sciences Center, Denver, Colorado 80262

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 5.6² µ 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.

Key words: oxytocin; receptor; substance P; supraoptic; vasopressin; neurokinin 3

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Received Aug 2, 2004; revised September 15, 2004; accepted September 23, 2004.

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				G. E. Haley and F. W. Flynn Tachykinin NK3 receptor contribution to systemic release of vasopressin and oxytocin in response to osmotic and hypotensive challenge Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2007; 293(2): R931 - R937. [Abstract] [Full Text] [PDF]

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