title: Neurokinin B and the hypothalamic regulation of reproduction.
abstract: Loss-of-function mutations in the genes encoding either neurokinin B (NKB) or its receptor, NK3 (NK3R), result in hypogonadotropic hypogonadism, characterized by an absence of pubertal development and low circulating levels of LH and gonadal steroids. These studies implicate NKB and NK3R as essential elements of the human reproductive axis. Studies over the last two decades provide evidence that a group of neurons in the hypothalamic infundibular/arcuate nucleus form an important component of this regulatory circuit. These neurons are steroid-responsive and coexpress NKB, kisspeptin, dynorphin, NK3R, and estrogen receptor α (ERα) in a variety of mammalian species. Compelling evidence in the human indicates these neurons function in the hypothalamic circuitry regulating estrogen negative feedback on gonadotropin-releasing hormone (GnRH) secretion. Moreover, in the rat, they form a bilateral, interconnected network that projects to NK3R-expressing GnRH terminals in the median eminence. This network provides an anatomical framework to explain how coordination among NKB/kisspeptin/dynorphin/NK3R/ERα neurons could mediate feedback information from the gonads to modulate pulsatile GnRH secretion. There is substantial (but indirect) evidence that this network may be part of the neural circuitry known as the "GnRH pulse generator," with NK3R signaling as an important component. This theory provides a compelling explanation for the occurrence of hypogonadotropic hypogonadism in patients with inactivating mutations in the TAC3 or TACR3 genes. Future studies will be needed to determine whether NKB signaling plays a permissive role in the onset of puberty or is part of the driving force initiating the maturation of reproductive function.
authors.affiliation: Department of Pathology, and the Evelyn F. McNight Brain Research Institute, University of Arizona College of Medicine, Tucson, AZ 85724, USA. nrance@email.arizona.edu
authors.forename: Naomi E
authors.initials: NE
authors.lastname: Rance
authors.forename: Sally J
authors.initials: SJ
authors.lastname: Krajewski
authors.forename: Melinda A
authors.initials: MA
authors.lastname: Smith
authors.forename: Marina
authors.initials: M
authors.lastname: Cholanian
authors.forename: Penny A
authors.initials: PA
authors.lastname: Dacks
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000166:cytology / Q000502:physiology; D004399:Dynorphins / Q000502:physiology; D004967:Estrogens / Q000502:physiology; D005260:Female; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D007031:Hypothalamus / Q000502:physiology*; D059648:Kisspeptins; D008253:Macaca mulatta; D008297:Male; D015287:Neurokinin B / Q000502:physiology*; D009474:Neurons / Q000502:physiology; D017698:Postmenopause / Q000502:physiology; D011247:Pregnancy; D018042:Receptors, Neurokinin-3 / Q000819:agonists / Q000235:genetics / Q000502:physiology; D012098:Reproduction / Q000502:physiology*; D012727:Sex Characteristics; D015398:Signal Transduction / Q000502:physiology; D009626:Terminology as Topic; D025521:Tumor Suppressor Proteins / Q000502:physiology
chemical_list: D004967:Estrogens; C106628:KISS1 protein, human; D059648:Kisspeptins; D018042:Receptors, Neurokinin-3; D025521:Tumor Suppressor Proteins; D004399:Dynorphins; D015287:Neurokinin B
references.citation: Endocrinology. 2000 Nov;141(11):4218-25
references.pmid: 11089556
references.citation: Endocrinology. 2002 Nov;143(11):4366-74
references.pmid: 12399433
references.citation: Front Neuroendocrinol. 2003 Apr;24(2):79-93
references.pmid: 12762999
references.citation: J Neurosci. 2005 Dec 7;25(49):11349-56
references.pmid: 16339030
references.citation: Neuroendocrinology. 1986;44(2):168-71
references.pmid: 3540699
references.citation: Endocrinology. 2004 Oct;145(10):4653-9
references.pmid: 15231708
references.citation: Nature. 2000 Jun 15;405(6788):797-800
references.pmid: 10866201
references.citation: Endocrinology. 2010 Aug;151(8):3836-46
references.pmid: 20519368
references.citation: Proc Natl Acad Sci U S A. 1986 Sep;83(18):7074-8
references.pmid: 3462746
references.citation: Brain Res. 2004 Nov 12;1026(2):307-12
references.pmid: 15488494
references.citation: J Comp Neurol. 1988 Jun 1;272(1):90-113
references.pmid: 2454979
references.citation: N Engl J Med. 2003 Oct 23;349(17):1614-27
references.pmid: 14573733
references.citation: Endocrinology. 2008 Aug;149(8):3926-32
references.pmid: 18450966
references.citation: Endocrinology. 1991 May;128(5):2239-47
references.pmid: 1708331
references.citation: Eur J Biochem. 1992 Mar 15;204(3):1025-33
references.pmid: 1312928
references.citation: J Neuroendocrinol. 2004 Oct;16(10):850-8
references.pmid: 15500545
references.citation: Endocrinology. 2010 Sep;151(9):4494-503
references.pmid: 20573725
references.citation: J Neurosci. 2009 Sep 23;29(38):11859-66
references.pmid: 19776272
references.citation: Pharmacol Rev. 1994 Dec;46(4):551-99
references.pmid: 7534932
references.citation: Am J Obstet Gynecol. 1990 Nov;163(5 Pt 2):1721-7
references.pmid: 2122728
references.citation: J Neurosci. 2009 Jul 22;29(29):9390-5
references.pmid: 19625529
references.citation: J Neurophysiol. 1995 Jan;73(1):56-64
references.pmid: 7714589
references.citation: J Comp Neurol. 1992 Mar 22;317(4):341-56
references.pmid: 1374442
references.citation: Endocrinology. 2005 Apr;146(4):1835-42
references.pmid: 15650077
references.citation: Curr Med Chem. 2004 Aug;11(15):2045-81
references.pmid: 15279567
references.citation: Mol Pharmacol. 1998 Jul;54(1):94-104
references.pmid: 9658194
references.citation: J Clin Endocrinol Metab. 2007 Mar;92(3):1137-44
references.pmid: 17164310
references.citation: Neuroendocrinology. 1991 Apr;53(4):392-5
references.pmid: 2046871
references.citation: J Physiol. 2002 Sep 15;543(Pt 3):1007-14
references.pmid: 12231654
references.citation: Am J Obstet Gynecol. 1977 Mar 15;127(6):581-4
references.pmid: 402812
references.citation: Endocrinology. 2008 Sep;149(9):4387-95
references.pmid: 18511511
references.citation: J Comp Neurol. 2000 Sep 4;424(4):679-88
references.pmid: 10931489
references.citation: J Comp Neurol. 2005 Aug 29;489(3):372-86
references.pmid: 16025449
references.citation: Endocrinology. 1999 Mar;140(3):1432-41
references.pmid: 10067872
references.citation: Hum Reprod. 2008 Mar;23(3):699-708
references.pmid: 18192670
references.citation: Eur J Neurosci. 2010 Jun;31(11):1984-98
references.pmid: 20529119
references.citation: Peptides. 2009 Aug;30(8):1508-13
references.pmid: 19433124
references.citation: Peptides. 2009 Jan;30(1):103-10
references.pmid: 18619506
references.citation: Endocrinology. 1982 Nov;111(5):1737-9
references.pmid: 6751801
references.citation: Neuroendocrinology. 1994 Oct;60(4):337-45
references.pmid: 7529897
references.citation: Pharmacol Res. 2004 Dec;50(6):611-5
references.pmid: 15501700
references.citation: Nat Genet. 2009 Mar;41(3):354-358
references.pmid: 19079066
references.citation: J Neuroendocrinol. 2006 Jul;18(7):534-41
references.pmid: 16774502
references.citation: Endocrinology. 2010 Aug;151(8):3479-89
references.pmid: 20501670
references.citation: Rev Reprod. 1999 May;4(2):110-6
references.pmid: 10357098
references.citation: Am J Physiol Regul Integr Comp Physiol. 2006 May;290(5):R1242-50
references.pmid: 16357093
references.citation: Endocrinology. 2004 Feb;145(2):736-42
references.pmid: 14592957
references.citation: J Neuroendocrinol. 2008 Dec;20(12):1376-81
references.pmid: 19094085
references.citation: J Neuroendocrinol. 2010 Mar;22(3):181-7
references.pmid: 20041982
references.citation: Rev Endocr Metab Disord. 2002 Sep;3(3):193-200
references.pmid: 12215714
references.citation: Endocrinology. 2010 Aug;151(8):3783-94
references.pmid: 20519367
references.citation: Biol Reprod. 1981 Feb;24(1):44-9
references.pmid: 6781549
references.citation: Neuroendocrinology. 2003 Oct;78(4):204-9
references.pmid: 14583652
references.citation: Neuron. 1996 Jul;17(1):135-45
references.pmid: 8755485
references.citation: Neuroscience. 2006 Sep 15;141(4):1731-45
references.pmid: 16809008
references.citation: J Clin Endocrinol Metab. 1990 Jul;71(1):79-85
references.pmid: 2370302
references.citation: Endocrinology. 2008 Aug;149(8):4151-7
references.pmid: 18450954
references.citation: J Comp Neurol. 1973 Sep 15;151(2):121-58
references.pmid: 4744471
references.citation: Psychopharmacology (Berl). 2007 Oct;194(2):185-95
references.pmid: 17558564
references.citation: Endocrinology. 2008 Mar;149(3):1004-8
references.pmid: 18063679
references.citation: J Neurosci. 2010 Feb 24;30(8):3124-32
references.pmid: 20181609
references.citation: J Clin Endocrinol Metab. 2007 Jul;92(7):2744-50
references.pmid: 17488799
references.citation: Curr Drug Targets. 2006 Aug;7(8):963-74
references.pmid: 16918325
references.citation: FASEB J. 1990 Apr 1;4(6):1606-15
references.pmid: 1969374
references.citation: Proc Natl Acad Sci U S A. 2009 Jun 30;106(26):10835-40
references.pmid: 19541658
references.citation: Endocrinology. 1978 Jan;102(1):52-62
references.pmid: 105866
references.citation: Neuroscience. 2000;98(4):801-11
references.pmid: 10891623
references.citation: J Comp Neurol. 1997 Aug 4;384(3):429-42
references.pmid: 9254037
references.citation: J Comp Neurol. 1996 Jan 08;364(2):290-310
references.pmid: 8788251
references.citation: Endocrinology. 2001 Jul;142(7):3261-4
references.pmid: 11416051
references.citation: Reprod Biol Endocrinol. 2010 Jan 14;8:4
references.pmid: 20074343
references.citation: Endocrinology. 2010 Jan;151(1):301-11
references.pmid: 19880810
references.citation: Neuroscience. 1992 Nov;51(2):317-45
references.pmid: 1465196
references.citation: J Comp Neurol. 2006 Oct 10;498(5):712-26
references.pmid: 16917850
references.citation: Endocrinology. 1979 Apr;104(4):940-7
references.pmid: 374065
references.citation: Brain Res Mol Brain Res. 1999 Mar 20;66(1-2):200-4
references.pmid: 10095095
references.citation: Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1852-5
references.pmid: 1542682
references.citation: Arch Histol Cytol. 2001 Feb;64(1):37-44
references.pmid: 11310503
references.citation: Brain Res. 1987 Sep;388(3):243-9
references.pmid: 3479225
references.citation: Regul Pept. 2001 Apr 20;98(3):97-104
references.pmid: 11231038
references.citation: Trends Pharmacol Sci. 1999 Apr;20(4):142-50
references.pmid: 10322499
references.citation: Ann N Y Acad Sci. 2003 Dec;1007:6-16
references.pmid: 14993035
references.citation: Neuroendocrinology. 1993 Apr;57(4):588-92
references.pmid: 8367027
references.citation: Trends Pharmacol Sci. 1995 Jul;16(7):232-8
references.pmid: 7667897
references.citation: J Clin Endocrinol Metab. 2009 Oct;94(10):3633-3639
references.pmid: 19755480
references.citation: Behav Pharmacol. 2008 Sep;19(5-6):518-29
references.pmid: 18690106
references.citation: Life Sci. 2004 Feb 6;74(12):1445-63
references.pmid: 14729395
references.citation: Endocrinology. 2004 Jun;145(6):2959-67
references.pmid: 14988383
references.citation: J Neuroendocrinol. 2010 Jul;22(7):825-32
references.pmid: 20646176
references.citation: J Clin Endocrinol Metab. 2002 Nov;87(11):5160-7
references.pmid: 12414887
references.citation: Brain. 1966 Sep;89(3):589-614
references.pmid: 5921130
references.citation: J Biol Chem. 1986 Aug 5;261(22):10257-63
references.pmid: 2426259
references.citation: J Clin Endocrinol Metab. 2005 Dec;90(12):6609-15
references.pmid: 16174713
references.citation: Neuroscience. 2007 May 11;146(2):630-42
references.pmid: 17395386
references.citation: J Neuroendocrinol. 2003 Aug;15(8):749-53
references.pmid: 12834435
references.citation: Am J Physiol Endocrinol Metab. 2009 Nov;297(5):E1212-21
references.pmid: 19755669
references.citation: Biochem Pharmacol. 2009 May 1;77(9):1522-30
references.pmid: 19426690
references.citation: Peptides. 2009 Jan;30(1):111-22
references.pmid: 18614256
references.citation: Cell Tissue Res. 2006 Jan;323(1):43-51
references.pmid: 16160861
references.citation: Peptides. 1992 Jul-Aug;13(4):815-29
references.pmid: 1437720
references.citation: Eur J Endocrinol. 2006 Nov;155 Suppl 1:S11-6
references.pmid: 17074983
references.citation: J Clin Endocrinol Metab. 1999 Jun;84(6):2111-8
references.pmid: 10372719
references.citation: Neurosci Biobehav Rev. 1995 Fall;19(3):427-37
references.pmid: 7566744
references.citation: Int J Biochem Cell Biol. 1996 Jul;28(7):721-38
references.pmid: 8925404
references.citation: J Neuroendocrinol. 2004 Feb;16(2):146-53
references.pmid: 14764001
references.citation: J Clin Endocrinol Metab. 1996 Oct;81(10):3540-6
references.pmid: 8855798
references.citation: Neuroscience. 2005;132(3):703-12
references.pmid: 15837132
references.citation: Endocr Rev. 2009 Oct;30(6):713-43
references.pmid: 19770291
references.citation: Proc Natl Acad Sci U S A. 1992 May 1;89(9):4149-53
references.pmid: 1570341
references.citation: Neurobiol Aging. 1993 Jul-Aug;14(4):337-42
references.pmid: 8367015
references.citation: J Clin Endocrinol Metab. 2010 May;95(5):2287-95
references.pmid: 20194706
references.citation: Neuroscience. 2010 Mar 17;166(2):680-97
references.pmid: 20038444
references.citation: J Clin Endocrinol Metab. 2010 Jun;95(6):2857-67
references.pmid: 20332248
references.citation: Proc Natl Acad Sci U S A. 1992 Sep 15;89(18):8462-6
references.pmid: 1326758
references.citation: Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10972-6
references.pmid: 12944565
references.citation: Neuroendocrinology. 1991 Jan;53(1):97-102
references.pmid: 2046864
references.citation: Endocrinology. 1981 Aug;109(2):376-85
references.pmid: 6788538
references.citation: Peptides. 2009 Jan;30(1):67-75
references.pmid: 18662732
references.citation: Cell Tissue Res. 2006 Nov;326(2):583-98
references.pmid: 16847638
references.citation: J Neuroendocrinol. 2010 Jan;22(1):1-12
references.pmid: 19912479
references.citation: J Comp Neurol. 1996 Aug 26;372(3):395-414
references.pmid: 8873868
references.citation: Endocrinology. 2007 Dec;148(12):5752-60
references.pmid: 17823266
references.citation: J Neuroendocrinol. 2009 Oct;21(10):813-21
references.pmid: 19678868
references.citation: FEBS Lett. 1985 Oct 7;190(1):133-6
references.pmid: 2995126
references.citation: Endocrinology. 2010 Jan;151(1):312-21
references.pmid: 19966188