Interactions between Two Different G Protein-Coupled Receptors in Reproductive Hormone-Producing Cells: The Role of PACAP and Its Receptor PAC1R.
Gonadotropin-releasing hormone (GnRH) and gonadotropins are indispensable hormones for maintaining female reproductive functions. In a similar manner to other endocrine hormones, GnRH and gonadotropins are controlled by their principle regulators. Although it has been previously established that GnRH regulates the synthesis and secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH)-both gonadotropins-from pituitary gonadotrophs, it has recently become clear that hypothalamic GnRH is under the control of hypothalamic kisspeptin. Prolactin, which is also known as luteotropic hormone and is released from pituitary lactotrophs, stimulates milk production in mammals. Prolactin is also regulated by hypothalamic factors, and it is thought that prolactin synthesis and release are principally under inhibitory control by dopamine through the dopamine D2 receptor. In addition, although it remains unknown whether it is a physiological regulator, thyrotropin-releasing hormone (TRH) is a strong secretagogue for prolactin. Thus, GnRH, LH and FSH, and prolactin are mainly regulated by hypothalamic kisspeptin, GnRH, and TRH, respectively. However, the synthesis and release of these hormones is also modulated by other neuropeptides in the hypothalamus. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a hypothalamic peptide that was first isolated from sheep hypothalamic extracts based on its ability to stimulate cAMP production in anterior pituitary cells. PACAP acts on GnRH neurons and pituitary gonadotrophs and lactotrophs, resulting in the modulation of their hormone producing/secreting functions. Furthermore, the presence of the PACAP type 1 receptor (PAC1R) has been demonstrated in these cells. We have examined how PACAP and PAC1R affect GnRH- and pituitary hormone-secreting cells and interact with their principle regulators. In this review, we describe our understanding of the role of PACAP and PAC1R in the regulation of GnRH neurons, gonadotrophs, and lactotrophs, which are regulated mainly by kisspeptin, GnRH, and TRH, respectively.
Department of Obstetrics and Gynecology, School of Medicine, Shimane University, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan. kanasaki@med.shimane-u.ac.jp.
Haruhiko
H
Kanasaki
Department of Obstetrics and Gynecology, School of Medicine, Shimane University, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan. oride@med.shimane-u.ac.jp.
Aki
A
Oride
Department of Obstetrics and Gynecology, School of Medicine, Shimane University, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan. t-hara@med.shimane-u.ac.jp.
Tomomi
T
Hara
Department of Obstetrics and Gynecology, School of Medicine, Shimane University, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan. tselmeg@med.shimane-u.ac.jp.
Tselmeg
T
Mijiddorj
Department of Obstetrics and Gynecology, School of Medicine, Shimane University, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan. unur@med.shimane-u.ac.jp.
Unurjargal
U
Sukhbaatar
Department of Obstetrics and Gynecology, School of Medicine, Shimane University, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan. kyo@med.shimane-u.ac.jp.
Satoru
S
Kyo
GnRH; PACAP; TRH; kisspeptin
J Neuroendocrinol. 2015 Jan;27(1):1-7
25303162
Gen Comp Endocrinol. 2013 Nov 1;193:95-102
23899713
Peptides. 2010 Sep;31(9):1748-55
20553777
Endocrinology. 2002 Mar;143(3):1018-25
11861527
J Comp Neurol. 1996 Aug 5;371(4):567-77
8841910
Biol Reprod. 2011 May;84(5):996-1004
21228211
Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1761-6
15665093
Brain Res Mol Brain Res. 1996 Sep 5;41(1-2):157-62
8883947
Endocrinology. 2001 Jul;142(7):2811-9
11416000
Annu Rev Physiol. 1986;48:515-26
3010825
Biol Reprod. 1999 Jul;61(1):319-25
10377065
J Neuroendocrinol. 1994 Oct;6(5):503-7
7827619
Peptides. 1998;19(6):1069-72
9700757
Biochem Biophys Res Commun. 2011 Jul 1;410(2):295-300
21658369
Endocrinology. 2001 May;142(5):1703-9
11316732
Genes Dev. 1997 Jan 15;11(2):167-78
9009200
N Engl J Med. 2003 Oct 23;349(17):1614-27
14573733
Mol Cell Endocrinol. 2009 Nov 13;311(1-2):126-34
19576263
Mol Cell Endocrinol. 2006 Sep 26;257-258:75-83
16930819
Endocrinology. 1996 Aug;137(8):3424-9
8754770
Endocrinology. 1981 Aug;109(2):376-85
6788538
Endocr Rev. 1990 Feb;11(1):177-99
2108012
Gen Comp Endocrinol. 2013 Dec 1;194:94-101
24055558
Endocrinology. 2008 Dec;149(12):6389-98
18755795
J Biol Chem. 2001 Sep 7;276(36):33319-27
11423551
Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10972-6
12944565
Endocrinology. 2005 Dec;146(12):5503-13
16141398
Mol Cell Endocrinol. 2011 Jun 6;339(1-2):172-9
21539889
Endocr Rev. 2001 Dec;22(6):724-63
11739329
Biol Reprod. 1981 Feb;24(1):44-9
6781549
Hum Reprod Update. 2014 Jul-Aug;20(4):485-500
24615662
Peptides. 1993 Jan-Feb;14(1):59-65
8441707
Recent Prog Horm Res. 1985;41:473-531
3931190
Regul Pept. 2002 Nov 15;109(1-3):49-55
12409214
Domest Anim Endocrinol. 1994 Oct;11(4):331-7
7828427
Biochemistry. 1975 Aug 26;14(17):3845-51
169886
Mol Cell Endocrinol. 2013 Jan 30;365(2):139-45
23103668
Endocrinology. 1996 Jan;137(1):304-11
8536629
J Comp Neurol. 1996 Dec 9;376(2):278-94
8951643
Brain Res. 1994 Aug 29;655(1-2):17-24
7812770
J Biol Chem. 2001 Sep 14;276(37):34631-6
11457843
J Neuroendocrinol. 2004 Oct;16(10):850-8
15500545
Semin Cell Dev Biol. 1998 Apr;9(2):143-52
9599409
Endocr Rev. 2000 Dec;21(6):619-70
11133067
Dev Cell. 2001 Oct;1(4):467-75
11703938
Endocrinology. 2003 Feb;144(2):612-22
12538624
J Neuroendocrinol. 2008 Jun;20(6):752-63
18601698
Endocr Rev. 1997 Feb;18(1):46-70
9034786
Proc Natl Acad Sci U S A. 1995 Dec 19;92(26):12280-4
8618885
Biol Reprod. 2007 Oct;77(4):707-16
17596563
Arch Med Res. 2001 Nov-Dec;32(6):499-509
11750725
Front Neuroendocrinol. 2015 Jan;36:15-27
24907402
J Biol Chem. 2002 Aug 30;277(35):32099-108
12050161
Regul Pept. 2011 Apr 11;167(2-3):227-32
21329727
Cancer Res. 2002 Oct 1;62(19):5399-404
12359743
Mol Cell Endocrinol. 2014 Jan 25;382(1):387-99
24145132
Biol Reprod. 2002 Jul;67(1):107-13
12080005
J Neurosci. 2008 Apr 23;28(17):4423-34
18434521
J Neuroendocrinol. 1997 Apr;9(4):279-86
9147291
Biochem Biophys Res Commun. 1971 May 7;43(3):516-23
4327442
Rev Med Inst Mex Seguro Soc. 2016 Jan-Feb;54(1):111-21
26820213
Endocrinology. 2002 May;143(5):1651-9
11956146
J Neurosci. 2005 Dec 7;25(49):11349-56
16339030
J Biol Chem. 1994 Feb 4;269(5):3783-8
7508919
Mol Endocrinol. 2009 Jul;23(7):1022-32
19342443
Neurosci Lett. 2011 Mar 29;492(1):55-8
21276835
Biol Reprod. 2009 Sep;81(3):465-72
19458315
Nature. 2001 May 31;411(6837):613-7
11385580
Regul Pept. 1995 Jan 26;55(2):133-48
7754101
Trends Endocrinol Metab. 1996 Jul;7(5):168-75
18406744
J Clin Endocrinol Metab. 1971 Dec;33(6):996-8
5002718
Exp Clin Endocrinol Diabetes. 1995;103(6):386-90
8788312
Pharmacol Rev. 2009 Sep;61(3):283-357
19805477
Hum Reprod Update. 2016 Apr;22(3):null
26715597
Biochem Biophys Res Commun. 1989 Oct 16;164(1):567-74
2803320
Fertil Steril. 1988 Mar;49(3):437-41
3342895
Recent Prog Horm Res. 1987;43:29-68
2819996
Mol Cell Endocrinol. 2008 Dec 16;296(1-2):78-86
18824214