KEGG   PATHWAY: uah04921
Entry
uah04921                    Pathway                                
Name
Oxytocin signaling pathway - Ursus arctos (brown bear)
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
uah04921  Oxytocin signaling pathway
uah04921

Organism
Ursus arctos (brown bear) [GN:uah]
Gene
113258188  OXT; oxytocin-neurophysin 1 [KO:K05243]
113257126  OXTR; oxytocin receptor [KO:K04229]
113269831  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
113257792  KRAS; GTPase KRas isoform X1 [KO:K07827]
113244394  NRAS; GTPase NRas isoform X2 [KO:K07828]
113257190  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X2 [KO:K04366] [EC:2.7.11.1]
113240885  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
113242822  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
113267646  MAPK3; LOW QUALITY PROTEIN: mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
113247020  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
113262763  PLA2G4A; cytosolic phospholipase A2 [KO:K16342] [EC:3.1.1.4]
113241915  PLA2G4F; cytosolic phospholipase A2 zeta [KO:K16342] [EC:3.1.1.4]
113241916  PLA2G4D; cytosolic phospholipase A2 delta [KO:K16342] [EC:3.1.1.4]
113241996  PLA2G4E; cytosolic phospholipase A2 epsilon isoform X1 [KO:K16342] [EC:3.1.1.4]
113262761  PTGS2; prostaglandin G/H synthase 2 [KO:K11987] [EC:1.14.99.1]
113271274  MAPK7; mitogen-activated protein kinase 7 [KO:K04464] [EC:2.7.11.24]
113254611  JUN; transcription factor Jun [KO:K04448]
113270317  FOS; protein c-Fos [KO:K04379]
113255121  MEF2C; myocyte-specific enhancer factor 2C isoform X1 [KO:K04454]
113243982  CCND1; G1/S-specific cyclin-D1 [KO:K04503]
113265986  ELK1; ETS domain-containing protein Elk-1 [KO:K04375]
113258943  RYR2; ryanodine receptor 2 isoform X1 [KO:K04962]
113242078  RYR3; ryanodine receptor 3 [KO:K04963]
113266704  CD38; ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 [KO:K01242] [EC:3.2.2.6 2.4.99.20]
113251377  TRPM2; transient receptor potential cation channel subfamily M member 2 isoform X1 [KO:K04977] [EC:3.6.1.13]
113265224  KCNJ2; inward rectifier potassium channel 2 [KO:K04996]
113271319  KCNJ12; ATP-sensitive inward rectifier potassium channel 12 [KO:K05005]
113241779  KCNJ4; inward rectifier potassium channel 4 [KO:K04998]
113243348  KCNJ14; ATP-sensitive inward rectifier potassium channel 14 [KO:K05007]
113244175  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
113258346  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 [KO:K05858] [EC:3.1.4.11]
113242038  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X1 [KO:K05858] [EC:3.1.4.11]
113265250  PRKCA; protein kinase C alpha type isoform X2 [KO:K02677] [EC:2.7.11.13]
113267584  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
113247385  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
113267554  EEF2K; eukaryotic elongation factor 2 kinase [KO:K08292] [EC:2.7.11.20]
113242819  EEF2; elongation factor 2 [KO:K03234]
113258052  CACNA1C; voltage-dependent L-type calcium channel subunit alpha-1C isoform X1 [KO:K04850]
113256986  CACNA1D; voltage-dependent L-type calcium channel subunit alpha-1D isoform X1 [KO:K04851]
113265950  CACNA1F; voltage-dependent L-type calcium channel subunit alpha-1F isoform X1 [KO:K04853]
113242563  CACNA1S; voltage-dependent L-type calcium channel subunit alpha-1S isoform X1 [KO:K04857]
113241360  CACNB2; voltage-dependent L-type calcium channel subunit beta-2 isoform X1 [KO:K04863]
113257670  CACNB3; voltage-dependent L-type calcium channel subunit beta-3 isoform X2 [KO:K04864]
113250882  CACNB4; voltage-dependent L-type calcium channel subunit beta-4 [KO:K04865]
113259255  CACNA2D1; voltage-dependent calcium channel subunit alpha-2/delta-1 isoform X7 [KO:K04858]
113256916  CACNA2D2; voltage-dependent calcium channel subunit alpha-2/delta-2 isoform X2 [KO:K04859]
113258103  CACNA2D4; voltage-dependent calcium channel subunit alpha-2/delta-4 [KO:K04861]
113265253  CACNG1; voltage-dependent calcium channel gamma-1 subunit [KO:K04866]
113267585  CACNG3; voltage-dependent calcium channel gamma-3 subunit [KO:K04868]
113265251  CACNG4; voltage-dependent calcium channel gamma-4 subunit [KO:K04869]
113265153  CACNG5; voltage-dependent calcium channel gamma-5 subunit [KO:K04870]
113247422  CACNG6; voltage-dependent calcium channel gamma-6 subunit [KO:K04871]
113257114  ITPR1; inositol 1,4,5-trisphosphate receptor type 1 [KO:K04958]
113257782  ITPR2; inositol 1,4,5-trisphosphate receptor type 2 isoform X1 [KO:K04959]
113243814  ITPR3; inositol 1,4,5-trisphosphate receptor type 3 isoform X1 [KO:K04960]
113241090  calmodulin-like [KO:K02183]
113241128  calmodulin-like protein 3 [KO:K02183]
113240902  CALML4; calmodulin-like protein 4 isoform X1 [KO:K02183]
113256068  calmodulin-1-like [KO:K02183]
113270001  PPP3CC; serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform isoform X2 [KO:K04348] [EC:3.1.3.16]
113263105  PPP3CA; protein phosphatase 3 catalytic subunit alpha isoform X1 [KO:K04348] [EC:3.1.3.16]
113260378  PPP3R2; calcineurin subunit B type 2 [KO:K06268]
113253544  NFATC1; nuclear factor of activated T-cells, cytoplasmic 1 isoform X1 [KO:K04446]
113258729  NFATC2; nuclear factor of activated T-cells, cytoplasmic 2 isoform X1 [KO:K17332]
113252399  NFATC3; nuclear factor of activated T-cells, cytoplasmic 3 isoform X1 [KO:K17333]
113246078  NFATC4; nuclear factor of activated T-cells, cytoplasmic 4 isoform X1 [KO:K17334]
113268748  RGS2; regulator of G-protein signaling 2 [KO:K18154]
113262509  RCAN1; calcipressin-1 isoform X1 [KO:K17901]
113266952  CAMKK2; calcium/calmodulin-dependent protein kinase kinase 2 isoform X1 [KO:K07359] [EC:2.7.11.17]
113260929  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
113254619  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
113247754  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X2 [KO:K07199]
113267029  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
113257659  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X2 [KO:K07200]
113241494  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X7 [KO:K07200]
113262641  CAMK1G; calcium/calmodulin-dependent protein kinase type 1G [KO:K08794] [EC:2.7.11.17]
113241069  CAMK1D; calcium/calmodulin-dependent protein kinase type 1D [KO:K08794] [EC:2.7.11.17]
113257142  CAMK1; calcium/calmodulin-dependent protein kinase type 1 isoform X2 [KO:K08794] [EC:2.7.11.17]
113257849  CAMK2B; LOW QUALITY PROTEIN: calcium/calmodulin-dependent protein kinase type II subunit beta [KO:K04515] [EC:2.7.11.17]
113255589  CAMK2D; calcium/calmodulin-dependent protein kinase type II subunit delta isoform X3 [KO:K04515] [EC:2.7.11.17]
113259192  CAMK2G; calcium/calmodulin-dependent protein kinase type II subunit gamma isoform X7 [KO:K04515] [EC:2.7.11.17]
113254999  CAMK4; calcium/calmodulin-dependent protein kinase type IV [KO:K05869] [EC:2.7.11.17]
113241474  NOS3; nitric oxide synthase, endothelial isoform X2 [KO:K13242] [EC:1.14.13.39]
113255781  GUCY1A1; guanylate cyclase soluble subunit alpha-1 [KO:K12318] [EC:4.6.1.2]
113260215  GUCY1A2; guanylate cyclase soluble subunit alpha-2 isoform X3 [KO:K12318] [EC:4.6.1.2]
113251013  guanylate cyclase soluble subunit beta-2 [KO:K12319] [EC:4.6.1.2]
113255783  GUCY1B1; guanylate cyclase soluble subunit beta-1 isoform X1 [KO:K12319] [EC:4.6.1.2]
113270670  NPPA; natriuretic peptides A [KO:K12334]
113245333  NPR1; atrial natriuretic peptide receptor 1 isoform X1 [KO:K12323] [EC:4.6.1.2]
113260460  NPR2; atrial natriuretic peptide receptor 2 isoform X1 [KO:K12324] [EC:4.6.1.2]
113264229  MYLK4; myosin light chain kinase family member 4 isoform X4 [KO:K00907] [EC:2.7.11.18]
113252202  MYLK3; myosin light chain kinase 3 isoform X1 [KO:K00907] [EC:2.7.11.18]
113252350  MYLK; myosin light chain kinase, smooth muscle isoform X3 [KO:K00907] [EC:2.7.11.18]
113258196  MYLK2; myosin light chain kinase 2, skeletal/cardiac muscle [KO:K00907] [EC:2.7.11.18]
113256435  MYL6B; myosin light chain 6B [KO:K12751]
113256436  MYL6; myosin light polypeptide 6 isoform X2 [KO:K12751]
113258556  MYL9; myosin regulatory light polypeptide 9 isoform X2 [KO:K12755]
113244519  ACTG1; actin, cytoplasmic 2 isoform X2 [KO:K05692]
113256876  RHOA; transforming protein RhoA [KO:K04513]
113253267  ROCK1; rho-associated protein kinase 1 isoform X1 [KO:K04514] [EC:2.7.11.1]
113269955  ROCK2; rho-associated protein kinase 2 [KO:K17388] [EC:2.7.11.1]
113244033  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
113266966  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
113256222  PPP1R12A; protein phosphatase 1 regulatory subunit 12A isoform X5 [KO:K06270]
113242537  PPP1R12B; protein phosphatase 1 regulatory subunit 12B isoform X7 [KO:K12329]
113247365  PPP1R12C; protein phosphatase 1 regulatory subunit 12C isoform X1 [KO:K17457]
113258768  GNAS; LOW QUALITY PROTEIN: guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas [KO:K04632]
113258223  neuroendocrine secretory protein 55 [KO:K04632]
113260807  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
113270586  ADCY3; adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
113246056  ADCY4; adenylate cyclase type 4 isoform X1 [KO:K08044] [EC:4.6.1.1]
113252326  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
113257671  ADCY6; adenylate cyclase type 6 isoform X1 [KO:K08046] [EC:4.6.1.1]
113252223  ADCY7; adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:4.6.1.1]
113252717  ADCY8; adenylate cyclase type 8 [KO:K08048] [EC:4.6.1.1]
113270857  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
113254486  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
113247197  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
113259201  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
113244920  GNAI3; guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
113256902  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
113252256  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha isoform X2 [KO:K04534]
113258627  PIK3CG; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform isoform X1 [KO:K21289] [EC:2.7.1.153]
113271195  PIK3R6; phosphoinositide 3-kinase regulatory subunit 6 [KO:K21290]
113271196  PIK3R5; phosphoinositide 3-kinase regulatory subunit 5 isoform X1 [KO:K21290]
113258578  SRC; proto-oncogene tyrosine-protein kinase Src [KO:K05704] [EC:2.7.10.2]
113250873  KCNJ3; G protein-activated inward rectifier potassium channel 1 isoform X1 [KO:K04997]
113258629  G protein-activated inward rectifier potassium channel 2 [KO:K05000]
113246727  KCNJ9; G protein-activated inward rectifier potassium channel 3 [KO:K05002]
113259740  KCNJ5; G protein-activated inward rectifier potassium channel 4 isoform X1 [KO:K04999]
113257444  EGFR; epidermal growth factor receptor isoform X1 [KO:K04361] [EC:2.7.10.1]
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
uah00590  Arachidonic acid metabolism
uah04010  MAPK signaling pathway
uah04020  Calcium signaling pathway
uah04110  Cell cycle
KO pathway
ko04921   
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