KEGG   PATHWAY: rno04929
Entry
rno04929                    Pathway                                

Name
GnRH secretion - Rattus norvegicus (rat)
Description
Hypothalamic gonadotropin-releasing hormone (GnRH) neurons are key regulators of reproduction. They release GnRH into the portal circulation. In turn, GnRH stimulates the pituitary gland to secrete follicle-stimulating hormone and luteinizing hormone (LH) to regulate gonadal functions. Gonadal steroids provide feedback to regulate GnRH release. GnRH neurons express the kisspeptin receptor, GPR 54, and kisspeptins potently stimulate the release of GnRH by depolarising and inducing sustained action potential firing in GnRH neurons. It is also demonstrated that Kisspeptin-GPR54 system positively regulates the GnRH expression  with a time course consistent with activation of Akt and MAP kinase signaling pathways.
Class
Organismal Systems; Endocrine system
Pathway map
rno04929  GnRH secretion
rno04929

Organism
Rattus norvegicus (rat) [GN:rno]
Gene
289023  Kiss1; metastasis-suppressor KiSS-1 precursor [KO:K23140]
78976  Kiss1r; kiSS-1 receptor isoform 1 [KO:K08374]
81666  Gnaq; guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
81662  Gna11; guanine nucleotide-binding protein subunit alpha-11 [KO:K04635]
24654  Plcb1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 [KO:K05858] [EC:3.1.4.11]
29322  Plcb3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
85240  Plcb2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:3.1.4.11]
25031  Plcb4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 [KO:K05858] [EC:3.1.4.11]
24680  Prkca; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
25023  Prkcb; protein kinase C beta type isoform 2 [KO:K19662] [EC:2.7.11.13]
24681  Prkcg; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
25262  Itpr1; inositol 1,4,5-trisphosphate receptor type 1 isoform 3 [KO:K04958]
81678  Itpr2; inositol 1,4,5-trisphosphate receptor type 2 [KO:K04959]
25679  Itpr3; inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960]
84390  Hcn1; potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1 [KO:K04954]
114244  Hcn2; potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2 [KO:K04955]
114245  Hcn3; potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 3 [KO:K04956]
29717  Cacna1g; voltage-dependent T-type calcium channel subunit alpha-1G isoform 1 [KO:K04854]
114862  Cacna1h; voltage-dependent T-type calcium channel subunit alpha-1H [KO:K04855]
56827  Cacna1i; voltage-dependent T-type calcium channel subunit alpha-1I [KO:K04856]
89821  Trpc1; short transient receptor potential channel 1 [KO:K04964]
84494  Trpc4; short transient receptor potential channel 4 isoform beta [KO:K04967]
140933  Trpc5; short transient receptor potential channel 5 [KO:K04968]
83535  Kcnj11; ATP-sensitive inward rectifier potassium channel 11 [KO:K05004]
50599  Kcnj3; G protein-activated inward rectifier potassium channel 1 [KO:K04997]
25743  Kcnj6; G protein-activated inward rectifier potassium channel 2 [KO:K05000]
116560  Kcnj9; G protein-activated inward rectifier potassium channel 3 [KO:K05002]
29713  Kcnj5; G protein-activated inward rectifier potassium channel 4 [KO:K04999]
81657  Gabbr1; gamma-aminobutyric acid type B receptor subunit 1 precursor [KO:K04615]
83633  Gabbr2; gamma-aminobutyric acid type B receptor subunit 2 precursor [KO:K04615]
54261  Kcnn1; small conductance calcium-activated potassium channel protein 1 [KO:K04942]
54262  Kcnn2; small conductance calcium-activated potassium channel protein 2 isoform 2 [KO:K04943]
54263  Kcnn3; small conductance calcium-activated potassium channel protein 3 [KO:K04944]
65206  Kcnn4; intermediate conductance calcium-activated potassium channel protein 4 isoform a [KO:K04945]
682930  Cacna1s; voltage-dependent L-type calcium channel subunit alpha-1S [KO:K04857]
24239  Cacna1c; voltage-dependent L-type calcium channel subunit alpha-1C [KO:K04850]
29716  Cacna1d; voltage-dependent L-type calcium channel subunit alpha-1D [KO:K04851]
114493  Cacna1f; voltage-dependent L-type calcium channel subunit alpha-1F [KO:K04853]
25387  Arrb1; beta-arrestin-1 [KO:K04439]
25388  Arrb2; beta-arrestin-2 [KO:K04439]
293621  Hras; GTPase HRas [KO:K02833]
367858  GTPase HRas [KO:K02833]
24525  Kras; GTPase KRas [KO:K07827]
24605  Nras; GTPase NRas [KO:K07828]
24703  Raf1; RAF proto-oncogene serine/threonine-protein kinase [KO:K04366] [EC:2.7.11.1]
170851  Map2k1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
58960  Map2k2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
116590  Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
50689  Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
25513  Pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
60664  Pik3r3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
29741  Pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
85243  Pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
170911  Pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
366508  Pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
24185  Akt1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
25233  Akt2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
29414  Akt3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
25194  Gnrh1; progonadoliberin-1 precursor [KO:K05252]
25149  Esr2; estrogen receptor beta [KO:K08551]
171104  Gper1; G-protein coupled estrogen receptor 1 [KO:K04246]
25329  Lhb; lutropin subunit beta isoform 1 precursor [KO:K08521]
25353  Spp1; osteopontin precursor [KO:K06250]
116700  Cga; glycoprotein hormones alpha chain precursor [KO:K08522]
Compound
C00076  Calcium cation
C00165  Diacylglycerol
C00238  Potassium cation
C00334  4-Aminobutanoate
C00535  Testosterone
C00951  Estradiol-17beta
C01245  D-myo-Inositol 1,4,5-trisphosphate
C01330  Sodium cation
C04637  1-Phosphatidyl-D-myo-inositol 4,5-bisphosphate
Reference
  Authors
Ronnekleiv OK, Kelly MJ
  Title
Kisspeptin excitation of GnRH neurons.
  Journal
Adv Exp Med Biol 784:113-31 (2013)
DOI:10.1007/978-1-4614-6199-9_6
Reference
  Authors
Beltramo M, Dardente H, Cayla X, Caraty A
  Title
Cellular mechanisms and integrative timing of neuroendocrine control of GnRH secretion by kisspeptin.
  Journal
Mol Cell Endocrinol 382:387-399 (2014)
DOI:10.1016/j.mce.2013.10.015
Reference
  Authors
Oakley AE, Clifton DK, Steiner RA
  Title
Kisspeptin signaling in the brain.
  Journal
Endocr Rev 30:713-43 (2009)
DOI:10.1210/er.2009-0005
Reference
  Authors
Pinilla L, Aguilar E, Dieguez C, Millar RP, Tena-Sempere M
  Title
Kisspeptins and reproduction: physiological roles and regulatory mechanisms.
  Journal
Physiol Rev 92:1235-316 (2012)
DOI:10.1152/physrev.00037.2010
Reference
  Authors
d'Anglemont de Tassigny X, Colledge WH
  Title
The role of kisspeptin signaling in reproduction.
  Journal
Physiology (Bethesda) 25:207-17 (2010)
DOI:10.1152/physiol.00009.2010
Reference
  Authors
Tena-Sempere M
  Title
Kisspeptin signaling in the brain: recent developments and future challenges.
  Journal
Mol Cell Endocrinol 314:164-9 (2010)
DOI:10.1016/j.mce.2009.05.004
Reference
  Authors
Colledge WH
  Title
Kisspeptins and GnRH neuronal signalling.
  Journal
Trends Endocrinol Metab 20:115-21 (2009)
DOI:10.1016/j.tem.2008.10.005
Reference
  Authors
Roa J, Castellano JM, Navarro VM, Handelsman DJ, Pinilla L, Tena-Sempere M
  Title
Kisspeptins and the control of gonadotropin secretion in male and female rodents.
  Journal
Peptides 30:57-66 (2009)
DOI:10.1016/j.peptides.2008.08.009
Reference
  Authors
Piet R, de Croft S, Liu X, Herbison AE
  Title
Electrical properties of kisspeptin neurons and their regulation of GnRH neurons.
  Journal
Front Neuroendocrinol 36:15-27 (2015)
DOI:10.1016/j.yfrne.2014.05.006
Reference
  Authors
Zhang C, Bosch MA, Ronnekleiv OK, Kelly MJ
  Title
Kisspeptin activation of TRPC4 channels in female GnRH neurons requires PIP2 depletion and cSrc kinase activation.
  Journal
Endocrinology 154:2772-83 (2013)
DOI:10.1210/en.2013-1180
Reference
  Authors
Ronnekleiv OK, Bosch MA, Zhang C
  Title
Regulation of endogenous conductances in GnRH neurons by estrogens.
  Journal
Brain Res 1364:25-34 (2010)
DOI:10.1016/j.brainres.2010.08.096
Reference
  Authors
Ronnekleiv OK, Zhang C, Bosch MA, Kelly MJ
  Title
Kisspeptin and Gonadotropin-Releasing Hormone Neuronal Excitability: Molecular Mechanisms Driven by 17beta-Estradiol.
  Journal
Neuroendocrinology 102:184-93 (2015)
DOI:10.1159/000370311
Reference
  Authors
Zhang XB, Spergel DJ
  Title
Kisspeptin inhibits high-voltage activated Ca2+ channels in GnRH neurons via multiple Ca2+ influx and release pathways.
  Journal
Neuroendocrinology 96:68-80 (2012)
DOI:10.1159/000335985
Reference
  Authors
Novaira HJ, Ng Y, Wolfe A, Radovick S
  Title
Kisspeptin increases GnRH mRNA expression and secretion in GnRH secreting neuronal cell lines.
  Journal
Mol Cell Endocrinol 311:126-34 (2009)
DOI:10.1016/j.mce.2009.06.011
Reference
  Authors
Glanowska KM, Moenter SM
  Title
Differential regulation of GnRH secretion in the preoptic area (POA) and the median eminence (ME) in male mice.
  Journal
Endocrinology 156:231-41 (2015)
DOI:10.1210/en.2014-1458
Reference
  Authors
Szereszewski JM, Pampillo M, Ahow MR, Offermanns S, Bhattacharya M, Babwah AV
  Title
GPR54 regulates ERK1/2 activity and hypothalamic gene expression in a Galpha(q/11) and beta-arrestin-dependent manner.
  Journal
PLoS One 5:e12964 (2010)
DOI:10.1371/journal.pone.0012964
Reference
  Authors
Zhang C, Bosch MA, Rick EA, Kelly MJ, Ronnekleiv OK
  Title
17Beta-estradiol regulation of T-type calcium channels in gonadotropin-releasing hormone neurons.
  Journal
J Neurosci 29:10552-62 (2009)
DOI:10.1523/JNEUROSCI.2962-09.2009
Reference
  Authors
Terasaka T, Otsuka F, Tsukamoto N, Nakamura E, Inagaki K, Toma K, Ogura-Ochi K, Glidewell-Kenney C, Lawson MA, Makino H
  Title
Mutual interaction of kisspeptin, estrogen and bone morphogenetic protein-4 activity in GnRH regulation by GT1-7 cells.
  Journal
Mol Cell Endocrinol 381:8-15 (2013)
DOI:10.1016/j.mce.2013.07.009
Reference
  Authors
Radovick S, Levine JE, Wolfe A
  Title
Estrogenic regulation of the GnRH neuron.
  Journal
Front Endocrinol (Lausanne) 3:52 (2012)
DOI:10.3389/fendo.2012.00052
Reference
  Authors
Dungan HM, Clifton DK, Steiner RA
  Title
Minireview: kisspeptin neurons as central processors in the regulation of gonadotropin-releasing hormone secretion.
  Journal
Endocrinology 147:1154-8 (2006)
DOI:10.1210/en.2005-1282
Reference
  Authors
Kato M, Tanaka N, Usui S, Sakuma Y
  Title
The SK channel blocker apamin inhibits slow afterhyperpolarization currents in rat gonadotropin-releasing hormone neurones.
  Journal
J Physiol 574:431-42 (2006)
DOI:10.1113/jphysiol.2006.110155
Reference
  Authors
Zhang C, Ronnekleiv OK, Kelly MJ
  Title
Kisspeptin inhibits a slow afterhyperpolarization current via protein kinase C and reduces spike frequency adaptation in GnRH neurons.
  Journal
Am J Physiol Endocrinol Metab 304:E1237-44 (2013)
DOI:10.1152/ajpendo.00058.2013
Related
pathway
rno04010  MAPK signaling pathway
rno04020  Calcium signaling pathway
rno04151  PI3K-Akt signaling pathway
rno04912  GnRH signaling pathway
rno04913  Ovarian steroidogenesis
rno04915  Estrogen signaling pathway
KO pathway
ko04929   

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