Neurokinin B and the hypothalamic regulation of reproduction.
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.
Rance
Naomi E
NE
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
Krajewski
Sally J
SJ
Smith
Melinda A
MA
Cholanian
Marina
M
Dacks
Penny A
PA
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
D004967:Estrogens; C106628:KISS1 protein, human; D059648:Kisspeptins; D018042:Receptors, Neurokinin-3; D025521:Tumor Suppressor Proteins; D004399:Dynorphins; D015287:Neurokinin B
Endocrinology. 2000 Nov;141(11):4218-25
11089556
Endocrinology. 2002 Nov;143(11):4366-74
12399433
Front Neuroendocrinol. 2003 Apr;24(2):79-93
12762999
J Neurosci. 2005 Dec 7;25(49):11349-56
16339030
Neuroendocrinology. 1986;44(2):168-71
3540699
Endocrinology. 2004 Oct;145(10):4653-9
15231708
Nature. 2000 Jun 15;405(6788):797-800
10866201
Endocrinology. 2010 Aug;151(8):3836-46
20519368
Proc Natl Acad Sci U S A. 1986 Sep;83(18):7074-8
3462746
Brain Res. 2004 Nov 12;1026(2):307-12
15488494
J Comp Neurol. 1988 Jun 1;272(1):90-113
2454979
N Engl J Med. 2003 Oct 23;349(17):1614-27
14573733
Endocrinology. 2008 Aug;149(8):3926-32
18450966
Endocrinology. 1991 May;128(5):2239-47
1708331
Eur J Biochem. 1992 Mar 15;204(3):1025-33
1312928
J Neuroendocrinol. 2004 Oct;16(10):850-8
15500545
Endocrinology. 2010 Sep;151(9):4494-503
20573725
J Neurosci. 2009 Sep 23;29(38):11859-66
19776272
Pharmacol Rev. 1994 Dec;46(4):551-99
7534932
Am J Obstet Gynecol. 1990 Nov;163(5 Pt 2):1721-7
2122728
J Neurosci. 2009 Jul 22;29(29):9390-5
19625529
J Neurophysiol. 1995 Jan;73(1):56-64
7714589
J Comp Neurol. 1992 Mar 22;317(4):341-56
1374442
Endocrinology. 2005 Apr;146(4):1835-42
15650077
Curr Med Chem. 2004 Aug;11(15):2045-81
15279567
Mol Pharmacol. 1998 Jul;54(1):94-104
9658194
J Clin Endocrinol Metab. 2007 Mar;92(3):1137-44
17164310
Neuroendocrinology. 1991 Apr;53(4):392-5
2046871
J Physiol. 2002 Sep 15;543(Pt 3):1007-14
12231654
Am J Obstet Gynecol. 1977 Mar 15;127(6):581-4
402812
Endocrinology. 2008 Sep;149(9):4387-95
18511511
J Comp Neurol. 2000 Sep 4;424(4):679-88
10931489
J Comp Neurol. 2005 Aug 29;489(3):372-86
16025449
Endocrinology. 1999 Mar;140(3):1432-41
10067872
Hum Reprod. 2008 Mar;23(3):699-708
18192670
Eur J Neurosci. 2010 Jun;31(11):1984-98
20529119
Peptides. 2009 Aug;30(8):1508-13
19433124
Peptides. 2009 Jan;30(1):103-10
18619506
Endocrinology. 1982 Nov;111(5):1737-9
6751801
Neuroendocrinology. 1994 Oct;60(4):337-45
7529897
Pharmacol Res. 2004 Dec;50(6):611-5
15501700
Nat Genet. 2009 Mar;41(3):354-358
19079066
J Neuroendocrinol. 2006 Jul;18(7):534-41
16774502
Endocrinology. 2010 Aug;151(8):3479-89
20501670
Rev Reprod. 1999 May;4(2):110-6
10357098
Am J Physiol Regul Integr Comp Physiol. 2006 May;290(5):R1242-50
16357093
Endocrinology. 2004 Feb;145(2):736-42
14592957
J Neuroendocrinol. 2008 Dec;20(12):1376-81
19094085
J Neuroendocrinol. 2010 Mar;22(3):181-7
20041982
Rev Endocr Metab Disord. 2002 Sep;3(3):193-200
12215714
Endocrinology. 2010 Aug;151(8):3783-94
20519367
Biol Reprod. 1981 Feb;24(1):44-9
6781549
Neuroendocrinology. 2003 Oct;78(4):204-9
14583652
Neuron. 1996 Jul;17(1):135-45
8755485
Neuroscience. 2006 Sep 15;141(4):1731-45
16809008
J Clin Endocrinol Metab. 1990 Jul;71(1):79-85
2370302
Endocrinology. 2008 Aug;149(8):4151-7
18450954
J Comp Neurol. 1973 Sep 15;151(2):121-58
4744471
Psychopharmacology (Berl). 2007 Oct;194(2):185-95
17558564
Endocrinology. 2008 Mar;149(3):1004-8
18063679
J Neurosci. 2010 Feb 24;30(8):3124-32
20181609
J Clin Endocrinol Metab. 2007 Jul;92(7):2744-50
17488799
Curr Drug Targets. 2006 Aug;7(8):963-74
16918325
FASEB J. 1990 Apr 1;4(6):1606-15
1969374
Proc Natl Acad Sci U S A. 2009 Jun 30;106(26):10835-40
19541658
Endocrinology. 1978 Jan;102(1):52-62
105866
Neuroscience. 2000;98(4):801-11
10891623
J Comp Neurol. 1997 Aug 4;384(3):429-42
9254037
J Comp Neurol. 1996 Jan 08;364(2):290-310
8788251
Endocrinology. 2001 Jul;142(7):3261-4
11416051
Reprod Biol Endocrinol. 2010 Jan 14;8:4
20074343
Endocrinology. 2010 Jan;151(1):301-11
19880810
Neuroscience. 1992 Nov;51(2):317-45
1465196
J Comp Neurol. 2006 Oct 10;498(5):712-26
16917850
Endocrinology. 1979 Apr;104(4):940-7
374065
Brain Res Mol Brain Res. 1999 Mar 20;66(1-2):200-4
10095095
Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1852-5
1542682
Arch Histol Cytol. 2001 Feb;64(1):37-44
11310503
Brain Res. 1987 Sep;388(3):243-9
3479225
Regul Pept. 2001 Apr 20;98(3):97-104
11231038
Trends Pharmacol Sci. 1999 Apr;20(4):142-50
10322499
Ann N Y Acad Sci. 2003 Dec;1007:6-16
14993035
Neuroendocrinology. 1993 Apr;57(4):588-92
8367027
Trends Pharmacol Sci. 1995 Jul;16(7):232-8
7667897
J Clin Endocrinol Metab. 2009 Oct;94(10):3633-3639
19755480
Behav Pharmacol. 2008 Sep;19(5-6):518-29
18690106
Life Sci. 2004 Feb 6;74(12):1445-63
14729395
Endocrinology. 2004 Jun;145(6):2959-67
14988383
J Neuroendocrinol. 2010 Jul;22(7):825-32
20646176
J Clin Endocrinol Metab. 2002 Nov;87(11):5160-7
12414887
Brain. 1966 Sep;89(3):589-614
5921130
J Biol Chem. 1986 Aug 5;261(22):10257-63
2426259
J Clin Endocrinol Metab. 2005 Dec;90(12):6609-15
16174713
Neuroscience. 2007 May 11;146(2):630-42
17395386
J Neuroendocrinol. 2003 Aug;15(8):749-53
12834435
Am J Physiol Endocrinol Metab. 2009 Nov;297(5):E1212-21
19755669
Biochem Pharmacol. 2009 May 1;77(9):1522-30
19426690
Peptides. 2009 Jan;30(1):111-22
18614256
Cell Tissue Res. 2006 Jan;323(1):43-51
16160861
Peptides. 1992 Jul-Aug;13(4):815-29
1437720
Eur J Endocrinol. 2006 Nov;155 Suppl 1:S11-6
17074983
J Clin Endocrinol Metab. 1999 Jun;84(6):2111-8
10372719
Neurosci Biobehav Rev. 1995 Fall;19(3):427-37
7566744
Int J Biochem Cell Biol. 1996 Jul;28(7):721-38
8925404
J Neuroendocrinol. 2004 Feb;16(2):146-53
14764001
J Clin Endocrinol Metab. 1996 Oct;81(10):3540-6
8855798
Neuroscience. 2005;132(3):703-12
15837132
Endocr Rev. 2009 Oct;30(6):713-43
19770291
Proc Natl Acad Sci U S A. 1992 May 1;89(9):4149-53
1570341
Neurobiol Aging. 1993 Jul-Aug;14(4):337-42
8367015
J Clin Endocrinol Metab. 2010 May;95(5):2287-95
20194706
Neuroscience. 2010 Mar 17;166(2):680-97
20038444
J Clin Endocrinol Metab. 2010 Jun;95(6):2857-67
20332248
Proc Natl Acad Sci U S A. 1992 Sep 15;89(18):8462-6
1326758
Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10972-6
12944565
Neuroendocrinology. 1991 Jan;53(1):97-102
2046864
Endocrinology. 1981 Aug;109(2):376-85
6788538
Peptides. 2009 Jan;30(1):67-75
18662732
Cell Tissue Res. 2006 Nov;326(2):583-98
16847638
J Neuroendocrinol. 2010 Jan;22(1):1-12
19912479
J Comp Neurol. 1996 Aug 26;372(3):395-414
8873868
Endocrinology. 2007 Dec;148(12):5752-60
17823266
J Neuroendocrinol. 2009 Oct;21(10):813-21
19678868
FEBS Lett. 1985 Oct 7;190(1):133-6
2995126
Endocrinology. 2010 Jan;151(1):312-21
19966188