KEGG   PATHWAY: ko04921
Entry
ko04921                     Pathway                                
Name
Oxytocin signaling pathway
Description
Oxytocin (OT) is a nonapeptide synthesized by the magno-cellular neurons located in the supraoptic (SON) and paraventricular (PVN) nuclei of the hypothalamus. It exerts a wide variety of central and peripheral effects. However, its best-known and most well-established roles are stimulation of uterine contractions during parturition and milk release during lactation. Oxytocin also influences cardiovascular regulation and various social behaviors. The actions of OT are all mediated by one type of OT receptor (OTR). This is a transmembrane receptor belonging to the G-protein-coupled receptor superfamily. The main signaling pathway is the Gq/PLC/Ins3 pathway, but the MAPK and the RhoA/Rho kinase pathways are also activated, contributing to increased prostaglandin production and direct contractile effect on myometrial cells. In the cardiovascular system, OTR is associated with the ANP-cGMP and NO-cGMP pathways, which reduce the force and rate of contraction and increase vasodilatation.
Class
Organismal Systems; Endocrine system
Pathway map
ko04921  Oxytocin signaling pathway
ko04921

Orthology
K00907  MYLK; myosin-light-chain kinase [EC:2.7.11.18]
K01242  CD38; ADP-ribosyl cyclase 1 [EC:3.2.2.6 2.4.99.20]
K02183  CALM; calmodulin
K02677  PRKCA; classical protein kinase C alpha type [EC:2.7.11.13]
K02833  HRAS; GTPase HRas
K03234  EEF2; elongation factor 2
K04229  OXTR; oxytocin receptor
K04345  PKA; protein kinase A [EC:2.7.11.11]
K04348  PPP3C, CNA; serine/threonine-protein phosphatase 2B catalytic subunit [EC:3.1.3.16]
K04361  EGFR, ERBB1; epidermal growth factor receptor [EC:2.7.10.1]
K04366  RAF1; RAF proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]
K04368  MAP2K1, MEK1; mitogen-activated protein kinase kinase 1 [EC:2.7.12.2]
K04369  MAP2K2, MEK2; mitogen-activated protein kinase kinase 2 [EC:2.7.12.2]
K04371  ERK, MAPK1_3; mitogen-activated protein kinase 1/3 [EC:2.7.11.24]
K04375  ELK1; ETS domain-containing protein Elk-1
K04379  FOS; proto-oncogene protein c-fos
K04446  NFATC1, NFAT2, NFATC; nuclear factor of activated T-cells, cytoplasmic 1
K04448  JUN; transcription factor AP-1
K04454  MEF2C; MADS-box transcription enhancer factor 2C
K04463  MAP2K5, MEK5; mitogen-activated protein kinase kinase 5 [EC:2.7.12.2]
K04464  MAPK7; mitogen-activated protein kinase 7 [EC:2.7.11.24]
K04503  CCND1; G1/S-specific cyclin-D1
K04513  RHOA; Ras homolog gene family, member A
K04514  ROCK1; Rho-associated protein kinase 1 [EC:2.7.11.39]
K04515  CAMK2; calcium/calmodulin-dependent protein kinase (CaM kinase) II [EC:2.7.11.17]
K04534  GNAO, G-ALPHA-O; guanine nucleotide-binding protein G(o) subunit alpha
K04630  GNAI; guanine nucleotide-binding protein G(i) subunit alpha
K04632  GNAS; guanine nucleotide-binding protein G(s) subunit alpha
K04634  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha
K04850  CACNA1C, CAV1.2; voltage-dependent calcium channel L type alpha-1C
K04851  CACNA1D, CAV1.3; voltage-dependent calcium channel L type alpha-1D
K04853  CACNA1F, CAV1.4; voltage-dependent calcium channel L type alpha-1F
K04857  CACNA1S, CAV1.1; voltage-dependent calcium channel L type alpha-1S
K04858  CACNA2D1; voltage-dependent calcium channel alpha-2/delta-1
K04859  CACNA2D2; voltage-dependent calcium channel alpha-2/delta-2
K04860  CACNA2D3; voltage-dependent calcium channel alpha-2/delta-3
K04861  CACNA2D4; voltage-dependent calcium channel alpha-2/delta-4
K04862  CACNB1; voltage-dependent calcium channel beta-1
K04863  CACNB2; voltage-dependent calcium channel beta-2
K04864  CACNB3; voltage-dependent calcium channel beta-3
K04865  CACNB4; voltage-dependent calcium channel beta-4
K04866  CACNG1; voltage-dependent calcium channel gamma-1
K04867  CACNG2; voltage-dependent calcium channel gamma-2
K04868  CACNG3; voltage-dependent calcium channel gamma-3
K04869  CACNG4; voltage-dependent calcium channel gamma-4
K04870  CACNG5; voltage-dependent calcium channel gamma-5
K04871  CACNG6; voltage-dependent calcium channel gamma-6
K04872  CACNG7; voltage-dependent calcium channel gamma-7
K04873  CACNG8; voltage-dependent calcium channel gamma-8
K04958  ITPR1; inositol 1,4,5-triphosphate receptor type 1
K04959  ITPR2; inositol 1,4,5-triphosphate receptor type 2
K04960  ITPR3; inositol 1,4,5-triphosphate receptor type 3
K04961  RYR1; ryanodine receptor 1
K04962  RYR2; ryanodine receptor 2
K04963  RYR3; ryanodine receptor 3
K04977  TRPM2; transient receptor potential cation channel subfamily M member 2 [EC:3.6.1.13]
K04996  KCNJ2, KIR2.1; potassium inwardly-rectifying channel subfamily J member 2
K04997  KCNJ3, KIR3.1; potassium inwardly-rectifying channel subfamily J member 3
K04998  KCNJ4, KIR2.3; potassium inwardly-rectifying channel subfamily J member 4
K04999  KCNJ5, KIR3.4; potassium inwardly-rectifying channel subfamily J member 5
K05000  KCNJ6, KIR3.2; potassium inwardly-rectifying channel subfamily J member 6
K05002  KCNJ9, KIR3.3; potassium inwardly-rectifying channel subfamily J member 9
K05005  KCNJ12_18, KIR2.2, KIR2.6; potassium inwardly-rectifying channel subfamily J member 12/18
K05007  KCNJ14, KIR2.4; potassium inwardly-rectifying channel subfamily J member 14
K05243  OXT; oxytocin-neurophysin 1
K05692  ACTB_G1; actin beta/gamma 1
K05704  SRC; tyrosine-protein kinase Src [EC:2.7.10.2]
K05858  PLCB; phosphatidylinositol phospholipase C, beta [EC:3.1.4.11]
K05869  CAMK4; calcium/calmodulin-dependent protein kinase IV [EC:2.7.11.17]
K06268  PPP3R, CNB; serine/threonine-protein phosphatase 2B regulatory subunit
K06269  PPP1C; serine/threonine-protein phosphatase PP1 catalytic subunit [EC:3.1.3.16]
K06270  PPP1R12A, MYPT1; protein phosphatase 1 regulatory subunit 12A
K06625  CDKN1A, P21, CIP1; cyclin-dependent kinase inhibitor 1A
K07198  PRKAA, AMPK; 5'-AMP-activated protein kinase, catalytic alpha subunit [EC:2.7.11.31]
K07199  PRKAB; 5'-AMP-activated protein kinase, regulatory beta subunit
K07200  PRKAG; 5'-AMP-activated protein kinase, regulatory gamma subunit
K07359  CAMKK2; calcium/calmodulin-dependent protein kinase kinase 2 [EC:2.7.11.17]
K07827  KRAS, KRAS2; GTPase KRas
K07828  NRAS; GTPase NRas
K08041  ADCY1; adenylate cyclase 1 [EC:4.6.1.1]
K08042  ADCY2; adenylate cyclase 2 [EC:4.6.1.1]
K08043  ADCY3; adenylate cyclase 3 [EC:4.6.1.1]
K08044  ADCY4; adenylate cyclase 4 [EC:4.6.1.1]
K08045  ADCY5; adenylate cyclase 5 [EC:4.6.1.1]
K08046  ADCY6; adenylate cyclase 6 [EC:4.6.1.1]
K08047  ADCY7; adenylate cyclase 7 [EC:4.6.1.1]
K08048  ADCY8; adenylate cyclase 8 [EC:4.6.1.1]
K08049  ADCY9; adenylate cyclase 9 [EC:4.6.1.1]
K08292  EEF2K; elongation factor 2 kinase [EC:2.7.11.20]
K08794  CAMK1; calcium/calmodulin-dependent protein kinase I [EC:2.7.11.17]
K11987  PTGS2, COX2; prostaglandin-endoperoxide synthase 2 [EC:1.14.99.1]
K12318  GUCY1A; guanylate cyclase soluble subunit alpha [EC:4.6.1.2]
K12319  GUCY1B; guanylate cyclase soluble subunit beta [EC:4.6.1.2]
K12323  ANPRA, NPR1; atrial natriuretic peptide receptor A [EC:4.6.1.2]
K12324  ANPRB, NPR2; atrial natriuretic peptide receptor B [EC:4.6.1.2]
K12329  PPP1R12B, MYPT2; protein phosphatase 1 regulatory subunit 12B
K12334  NPPA; natriuretic peptide A
K12751  MYL6; myosin light chain 6
K12755  MYL9; myosin regulatory light chain 9
K13242  NOS3; nitric-oxide synthase, endothelial [EC:1.14.13.39]
K16342  PLA2G4, CPLA2; cytosolic phospholipase A2 [EC:3.1.1.4]
K17332  NFATC2, NFAT1, NFATP; nuclear factor of activated T-cells, cytoplasmic 2
K17333  NFATC3, NFAT4; nuclear factor of activated T-cells, cytoplasmic 3
K17334  NFATC4, NFAT3; nuclear factor of activated T-cells, cytoplasmic 4
K17388  ROCK2; Rho-associated protein kinase 2 [EC:2.7.11.39]
K17457  PPP1R12C, MBS85; protein phosphatase 1 regulatory subunit 12C
K17901  RCAN1, MCIP1; calcipressin-1
K18154  RGS2; regulator of G-protein signaling 2
K19662  PRKCB; classical protein kinase C beta type [EC:2.7.11.13]
K19663  PRKCG; classical protein kinase C gamma type [EC:2.7.11.13]
K21289  PIK3CG; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma [EC:2.7.1.153]
K21290  PIK3R5_6; phosphoinositide-3-kinase regulatory subunit 5/6
Compound
C00076  Calcium cation
C00165  Diacylglycerol
C00219  Arachidonate
C00238  Potassium cation
C00427  Prostaglandin H2
C00533  Nitric oxide
C00575  3',5'-Cyclic AMP
C00584  Prostaglandin E2
C00639  Prostaglandin F2alpha
C00942  3',5'-Cyclic GMP
C01245  D-myo-Inositol 1,4,5-trisphosphate
C13050  Cyclic ADP-ribose
Reference
PMID:18655881
  Authors
Devost D, Wrzal P, Zingg HH
  Title
Oxytocin receptor signalling.
  Journal
Prog Brain Res 170:167-76 (2008)
DOI:10.1016/S0079-6123(08)00415-9
Reference
PMID:20626426
  Authors
Viero C, Shibuya I, Kitamura N, Verkhratsky A, Fujihara H, Katoh A, Ueta Y, Zingg HH, Chvatal A, Sykova E, Dayanithi G
  Title
REVIEW: Oxytocin: Crossing the bridge between basic science and pharmacotherapy.
  Journal
CNS Neurosci Ther 16:e138-56 (2010)
DOI:10.1111/j.1755-5949.2010.00185.x
Reference
PMID:21981277
  Authors
Gutkowska J, Jankowski M
  Title
Oxytocin revisited: its role in cardiovascular regulation.
  Journal
J Neuroendocrinol 24:599-608 (2012)
DOI:10.1111/j.1365-2826.2011.02235.x
Reference
PMID:22190926
  Authors
Vrachnis N, Malamas FM, Sifakis S, Deligeoroglou E, Iliodromiti Z
  Title
The oxytocin-oxytocin receptor system and its antagonists as tocolytic agents.
  Journal
Int J Endocrinol 2011:350546 (2011)
DOI:10.1155/2011/350546
Reference
PMID:19840865
  Authors
Tom N, Assinder SJ
  Title
Oxytocin in health and disease.
  Journal
Int J Biochem Cell Biol 42:202-5 (2010)
DOI:10.1016/j.biocel.2009.10.008
Reference
PMID:9575824
  Authors
Strakova Z, Copland JA, Lolait SJ, Soloff MS
  Title
ERK2 mediates oxytocin-stimulated PGE2 synthesis.
  Journal
Am J Physiol 274:E634-41 (1998)
DOI:10.1152/ajpendo.1998.274.4.E634
Reference
PMID:12009385
  Authors
Slater DM, Zervou S, Thornton S
  Title
Prostaglandins and prostanoid receptors in human pregnancy and parturition.
  Journal
J Soc Gynecol Investig 9:118-24 (2002)
Reference
PMID:16787565
  Authors
Shmygol A, Gullam J, Blanks A, Thornton S
  Title
Multiple mechanisms involved in oxytocin-induced modulation of myometrial contractility.
  Journal
Acta Pharmacol Sin 27:827-32 (2006)
DOI:10.1111/j.1745-7254.2006.00393.x
Reference
PMID:11861513
  Authors
Tahara M, Morishige K, Sawada K, Ikebuchi Y, Kawagishi R, Tasaka K, Murata Y
  Title
RhoA/Rho-kinase cascade is involved in oxytocin-induced rat uterine contraction.
  Journal
Endocrinology 143:920-9 (2002)
DOI:10.1210/endo.143.3.8696
Reference
PMID:12433531
  Authors
Slattery MM, Morrison JJ
  Title
Preterm delivery.
  Journal
Lancet 360:1489-97 (2002)
DOI:10.1016/S0140-6736(02)11476-0
Reference
PMID:22902539
  Authors
Pont JN, McArdle CA, Lopez Bernal A
  Title
Oxytocin-stimulated NFAT transcriptional activation in human myometrial cells.
  Journal
Mol Endocrinol 26:1743-56 (2012)
DOI:10.1210/me.2012-1057
Reference
PMID:9326674
  Authors
Gutkowska J, Jankowski M, Lambert C, Mukaddam-Daher S, Zingg HH, McCann SM
  Title
Oxytocin releases atrial natriuretic peptide by combining with oxytocin receptors in the heart.
  Journal
Proc Natl Acad Sci U S A 94:11704-9 (1997)
DOI:10.1073/pnas.94.21.11704
Reference
PMID:14715914
  Authors
Antunes-Rodrigues J, de Castro M, Elias LL, Valenca MM, McCann SM
  Title
Neuroendocrine control of body fluid metabolism.
  Journal
Physiol Rev 84:169-208 (2004)
DOI:10.1152/physrev.00017.2003
Reference
PMID:18555543
  Authors
Lee ES, Uhm KO, Lee YM, Kwon J, Park SH, Soo KH
  Title
Oxytocin stimulates glucose uptake in skeletal muscle cells through the calcium-CaMKK-AMPK pathway.
  Journal
Regul Pept 151:71-4 (2008)
DOI:10.1016/j.regpep.2008.05.001
Reference
PMID:9219843
  Authors
Cassoni P, Sapino A, Fortunati N, Munaron L, Chini B, Bussolati G
  Title
Oxytocin inhibits the proliferation of MDA-MB231 human breast-cancer cells via cyclic adenosine monophosphate and protein kinase A.
  Journal
Int J Cancer 72:340-4 (1997)
DOI:10.1002/(SICI)1097-0215(19970717)72:2<340::AID-IJC23>3.0.CO;2-I
Reference
PMID:23356278
  Authors
Busnelli M, Peverelli E, Mantovani G, Spada A, Chini B
  Title
Deciphering the specific role of G(alphai/o) isoforms: functional selective oxytocin ligands and somatostatin SST5 receptor mutants.
  Journal
Biochem Soc Trans 41:166-71 (2013)
DOI:10.1042/BST20120306
Reference
PMID:16966388
  Authors
Reversi A, Rimoldi V, Brambillasca S, Chini B
  Title
Effects of cholesterol manipulation on the signaling of the human oxytocin receptor.
  Journal
Am J Physiol Regul Integr Comp Physiol 291:R861-9 (2006)
DOI:10.1152/ajpregu.00333.2006
Reference
PMID:20141572
  Authors
Salmina AB, Lopatina O, Ekimova MV, Mikhutkina SV, Higashida H
  Title
CD38/cyclic ADP-ribose system: a new player for oxytocin secretion and regulation of social behaviour.
  Journal
J Neuroendocrinol 22:380-92 (2010)
DOI:10.1111/j.1365-2826.2010.01970.x
Reference
PMID:22227279
  Authors
Higashida H, Yokoyama S, Kikuchi M, Munesue T
  Title
CD38 and its role in oxytocin secretion and social behavior.
  Journal
Horm Behav 61:351-8 (2012)
DOI:10.1016/j.yhbeh.2011.12.011
Reference
PMID:23335873
  Authors
Lopatina O, Inzhutova A, Salmina AB, Higashida H
  Title
The roles of oxytocin and CD38 in social or parental behaviors.
  Journal
Front Neurosci 6:182 (2012)
DOI:10.3389/fnins.2012.00182
Reference
PMID:16156781
  Authors
Guse AH
  Title
Second messenger function and the structure-activity relationship of cyclic adenosine diphosphoribose (cADPR).
  Journal
FEBS J 272:4590-7 (2005)
DOI:10.1111/j.1742-4658.2005.04863.x
Related
pathway
ko00590  Arachidonic acid metabolism
ko04010  MAPK signaling pathway
ko04020  Calcium signaling pathway
ko04110  Cell cycle

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