KEGG   PATHWAY: mmu04921
Entry
mmu04921                    Pathway                                
Name
Oxytocin signaling pathway - Mus musculus (house mouse)
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
mmu04921  Oxytocin signaling pathway
mmu04921

Organism
Mus musculus (house mouse) [GN:mmu]
Gene
18429  Oxt; oxytocin [KO:K05243]
18430  Oxtr; oxytocin receptor [KO:K04229]
14682  Gnaq; guanine nucleotide binding protein, alpha q polypeptide [KO:K04634]
15461  Hras; Harvey rat sarcoma virus oncogene [KO:K02833]
16653  Kras; Kirsten rat sarcoma viral oncogene homolog [KO:K07827]
18176  Nras; neuroblastoma ras oncogene [KO:K07828]
110157  Raf1; v-raf-leukemia viral oncogene 1 [KO:K04366] [EC:2.7.11.1]
26395  Map2k1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
26396  Map2k2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
26413  Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
26417  Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
329502  Pla2g4e; phospholipase A2, group IVE [KO:K16342] [EC:3.1.1.4]
18783  Pla2g4a; phospholipase A2, group IVA (cytosolic, calcium-dependent) [KO:K16342] [EC:3.1.1.4]
211429  Pla2g4b; phospholipase A2, group IVB (cytosolic) [KO:K16342] [EC:3.1.1.4]
232889  Pla2g4c; phospholipase A2, group IVC (cytosolic, calcium-independent) [KO:K16342] [EC:3.1.1.4]
78390  Pla2g4d; phospholipase A2, group IVD [KO:K16342] [EC:3.1.1.4]
271844  Pla2g4f; phospholipase A2, group IVF [KO:K16342] [EC:3.1.1.4]
19225  Ptgs2; prostaglandin-endoperoxide synthase 2 [KO:K11987] [EC:1.14.99.1]
23938  Map2k5; mitogen-activated protein kinase kinase 5 [KO:K04463] [EC:2.7.12.2]
23939  Mapk7; mitogen-activated protein kinase 7 [KO:K04464] [EC:2.7.11.24]
16476  Jun; jun proto-oncogene [KO:K04448]
14281  Fos; FBJ osteosarcoma oncogene [KO:K04379]
17260  Mef2c; myocyte enhancer factor 2C [KO:K04454]
12443  Ccnd1; cyclin D1 [KO:K04503]
13712  Elk1; ELK1, member of ETS oncogene family [KO:K04375]
20190  Ryr1; ryanodine receptor 1, skeletal muscle [KO:K04961]
20191  Ryr2; ryanodine receptor 2, cardiac [KO:K04962]
20192  Ryr3; ryanodine receptor 3 [KO:K04963]
12494  Cd38; CD38 antigen [KO:K01242] [EC:3.2.2.6 2.4.99.20]
28240  Trpm2; transient receptor potential cation channel, subfamily M, member 2 [KO:K04977] [EC:3.6.1.13]
16518  Kcnj2; potassium inwardly-rectifying channel, subfamily J, member 2 [KO:K04996]
16515  Kcnj12; potassium inwardly-rectifying channel, subfamily J, member 12 [KO:K05005]
16520  Kcnj4; potassium inwardly-rectifying channel, subfamily J, member 4 [KO:K04998]
211480  Kcnj14; potassium inwardly-rectifying channel, subfamily J, member 14 [KO:K05007]
18795  Plcb1; phospholipase C, beta 1 [KO:K05858] [EC:3.1.4.11]
18797  Plcb3; phospholipase C, beta 3 [KO:K05858] [EC:3.1.4.11]
18798  Plcb4; phospholipase C, beta 4 [KO:K05858] [EC:3.1.4.11]
18796  Plcb2; phospholipase C, beta 2 [KO:K05858] [EC:3.1.4.11]
18750  Prkca; protein kinase C, alpha [KO:K02677] [EC:2.7.11.13]
18751  Prkcb; protein kinase C, beta [KO:K19662] [EC:2.7.11.13]
18752  Prkcg; protein kinase C, gamma [KO:K19663] [EC:2.7.11.13]
13631  Eef2k; eukaryotic elongation factor-2 kinase [KO:K08292] [EC:2.7.11.20]
13629  Eef2; eukaryotic translation elongation factor 2 [KO:K03234]
12288  Cacna1c; calcium channel, voltage-dependent, L type, alpha 1C subunit [KO:K04850]
12289  Cacna1d; calcium channel, voltage-dependent, L type, alpha 1D subunit [KO:K04851]
54652  Cacna1f; calcium channel, voltage-dependent, alpha 1F subunit [KO:K04853]
12292  Cacna1s; calcium channel, voltage-dependent, L type, alpha 1S subunit [KO:K04857]
12295  Cacnb1; calcium channel, voltage-dependent, beta 1 subunit [KO:K04862]
12296  Cacnb2; calcium channel, voltage-dependent, beta 2 subunit [KO:K04863]
12297  Cacnb3; calcium channel, voltage-dependent, beta 3 subunit [KO:K04864]
12298  Cacnb4; calcium channel, voltage-dependent, beta 4 subunit [KO:K04865]
12293  Cacna2d1; calcium channel, voltage-dependent, alpha2/delta subunit 1 [KO:K04858]
56808  Cacna2d2; calcium channel, voltage-dependent, alpha 2/delta subunit 2 [KO:K04859]
12294  Cacna2d3; calcium channel, voltage-dependent, alpha2/delta subunit 3 [KO:K04860]
319734  Cacna2d4; calcium channel, voltage-dependent, alpha 2/delta subunit 4 [KO:K04861]
12299  Cacng1; calcium channel, voltage-dependent, gamma subunit 1 [KO:K04866]
12300  Cacng2; calcium channel, voltage-dependent, gamma subunit 2 [KO:K04867]
54376  Cacng3; calcium channel, voltage-dependent, gamma subunit 3 [KO:K04868]
54377  Cacng4; calcium channel, voltage-dependent, gamma subunit 4 [KO:K04869]
140723  Cacng5; calcium channel, voltage-dependent, gamma subunit 5 [KO:K04870]
54378  Cacng6; calcium channel, voltage-dependent, gamma subunit 6 [KO:K04871]
81904  Cacng7; calcium channel, voltage-dependent, gamma subunit 7 [KO:K04872]
81905  Cacng8; calcium channel, voltage-dependent, gamma subunit 8 [KO:K04873]
16438  Itpr1; inositol 1,4,5-trisphosphate receptor 1 [KO:K04958]
16439  Itpr2; inositol 1,4,5-triphosphate receptor 2 [KO:K04959]
16440  Itpr3; inositol 1,4,5-triphosphate receptor 3 [KO:K04960]
12313  Calm1; calmodulin 1 [KO:K02183]
80796  Calm4; calmodulin 4 [KO:K02183]
12315  Calm3; calmodulin 3 [KO:K02183]
12314  Calm2; calmodulin 2 [KO:K02183]
70405  Calml3; calmodulin-like 3 [KO:K02183]
494124  Calm5; calmodulin 5 [KO:K02183]
75600  Calml4; calmodulin-like 4 [KO:K02183]
19057  Ppp3cc; protein phosphatase 3, catalytic subunit, gamma isoform [KO:K04348] [EC:3.1.3.16]
19055  Ppp3ca; protein phosphatase 3, catalytic subunit, alpha isoform [KO:K04348] [EC:3.1.3.16]
19056  Ppp3cb; protein phosphatase 3, catalytic subunit, beta isoform [KO:K04348] [EC:3.1.3.16]
19058  Ppp3r1; protein phosphatase 3, regulatory subunit B, alpha isoform (calcineurin B, type I) [KO:K06268]
19059  Ppp3r2; protein phosphatase 3, regulatory subunit B, alpha isoform (calcineurin B, type II) [KO:K06268]
18018  Nfatc1; nuclear factor of activated T cells, cytoplasmic, calcineurin dependent 1 [KO:K04446]
18019  Nfatc2; nuclear factor of activated T cells, cytoplasmic, calcineurin dependent 2 [KO:K17332]
18021  Nfatc3; nuclear factor of activated T cells, cytoplasmic, calcineurin dependent 3 [KO:K17333]
73181  Nfatc4; nuclear factor of activated T cells, cytoplasmic, calcineurin dependent 4 [KO:K17334]
19735  Rgs2; regulator of G-protein signaling 2 [KO:K18154]
54720  Rcan1; regulator of calcineurin 1 [KO:K17901]
207565  Camkk2; calcium/calmodulin-dependent protein kinase kinase 2, beta [KO:K07359] [EC:2.7.11.17]
105787  Prkaa1; protein kinase, AMP-activated, alpha 1 catalytic subunit [KO:K07198] [EC:2.7.11.31]
108079  Prkaa2; protein kinase, AMP-activated, alpha 2 catalytic subunit [KO:K07198] [EC:2.7.11.31]
19079  Prkab1; protein kinase, AMP-activated, beta 1 non-catalytic subunit [KO:K07199]
108097  Prkab2; protein kinase, AMP-activated, beta 2 non-catalytic subunit [KO:K07199]
19082  Prkag1; protein kinase, AMP-activated, gamma 1 non-catalytic subunit [KO:K07200]
241113  Prkag3; protein kinase, AMP-activated, gamma 3 non-catalytic subunit [KO:K07200]
108099  Prkag2; protein kinase, AMP-activated, gamma 2 non-catalytic subunit [KO:K07200]
215303  Camk1g; calcium/calmodulin-dependent protein kinase I gamma [KO:K08794] [EC:2.7.11.17]
52163  Camk1; calcium/calmodulin-dependent protein kinase I [KO:K08794] [EC:2.7.11.17]
108058  Camk2d; calcium/calmodulin-dependent protein kinase II, delta [KO:K04515] [EC:2.7.11.17]
12325  Camk2g; calcium/calmodulin-dependent protein kinase II gamma [KO:K04515] [EC:2.7.11.17]
12323  Camk2b; calcium/calmodulin-dependent protein kinase II, beta [KO:K04515] [EC:2.7.11.17]
12322  Camk2a; calcium/calmodulin-dependent protein kinase II alpha [KO:K04515] [EC:2.7.11.17]
12326  Camk4; calcium/calmodulin-dependent protein kinase IV [KO:K05869] [EC:2.7.11.17]
18127  Nos3; nitric oxide synthase 3, endothelial cell [KO:K13242] [EC:1.14.13.39]
60596  Gucy1a1; guanylate cyclase 1, soluble, alpha 1 [KO:K12318] [EC:4.6.1.2]
234889  Gucy1a2; guanylate cyclase 1, soluble, alpha 2 [KO:K12318] [EC:4.6.1.2]
239134  Gucy1b2; guanylate cyclase 1, soluble, beta 2 [KO:K12319] [EC:4.6.1.2]
54195  Gucy1b1; guanylate cyclase 1, soluble, beta 1 [KO:K12319] [EC:4.6.1.2]
230899  Nppa; natriuretic peptide type A [KO:K12334]
18160  Npr1; natriuretic peptide receptor 1 [KO:K12323] [EC:4.6.1.2]
230103  Npr2; natriuretic peptide receptor 2 [KO:K12324] [EC:4.6.1.2]
107589  Mylk; myosin, light polypeptide kinase [KO:K00907] [EC:2.7.11.18]
213435  Mylk3; myosin light chain kinase 3 [KO:K00907] [EC:2.7.11.18]
228785  Mylk2; myosin, light polypeptide kinase 2, skeletal muscle [KO:K00907] [EC:2.7.11.18]
238564  Mylk4; myosin light chain kinase family, member 4 [KO:K00907] [EC:2.7.11.18]
17904  Myl6; myosin, light polypeptide 6, alkali, smooth muscle and non-muscle [KO:K12751]
216459  Myl6b; myosin, light polypeptide 6B [KO:K12751]
98932  Myl9; myosin, light polypeptide 9, regulatory [KO:K12755]
11465  Actg1; actin, gamma, cytoplasmic 1 [KO:K05692]
11461  Actb; actin, beta [KO:K05692]
11848  Rhoa; ras homolog family member A [KO:K04513]
67653  4930544G11Rik; RIKEN cDNA 4930544G11 gene [KO:K04513]
19877  Rock1; Rho-associated coiled-coil containing protein kinase 1 [KO:K04514] [EC:2.7.11.1]
19878  Rock2; Rho-associated coiled-coil containing protein kinase 2 [KO:K17388] [EC:2.7.11.1]
19045  Ppp1ca; protein phosphatase 1 catalytic subunit alpha [KO:K06269] [EC:3.1.3.16]
19046  Ppp1cb; protein phosphatase 1 catalytic subunit beta [KO:K06269] [EC:3.1.3.16]
19047  Ppp1cc; protein phosphatase 1 catalytic subunit gamma [KO:K06269] [EC:3.1.3.16]
434233  Ppp1ccb; protein phosphatase 1 catalytic subunit gamma B [KO:K06269] [EC:3.1.3.16]
17931  Ppp1r12a; protein phosphatase 1, regulatory subunit 12A [KO:K06270]
329251  Ppp1r12b; protein phosphatase 1, regulatory subunit 12B [KO:K12329]
232807  Ppp1r12c; protein phosphatase 1, regulatory subunit 12C [KO:K17457]
14683  Gnas; GNAS complex locus [KO:K04632]
432530  Adcy1; adenylate cyclase 1 [KO:K08041] [EC:4.6.1.1]
210044  Adcy2; adenylate cyclase 2 [KO:K08042] [EC:4.6.1.1]
104111  Adcy3; adenylate cyclase 3 [KO:K08043] [EC:4.6.1.1]
104110  Adcy4; adenylate cyclase 4 [KO:K08044] [EC:4.6.1.1]
224129  Adcy5; adenylate cyclase 5 [KO:K08045] [EC:4.6.1.1]
11512  Adcy6; adenylate cyclase 6 [KO:K08046] [EC:4.6.1.1]
11513  Adcy7; adenylate cyclase 7 [KO:K08047] [EC:4.6.1.1]
11514  Adcy8; adenylate cyclase 8 [KO:K08048] [EC:4.6.1.1]
11515  Adcy9; adenylate cyclase 9 [KO:K08049] [EC:4.6.1.1]
18747  Prkaca; protein kinase, cAMP dependent, catalytic, alpha [KO:K04345] [EC:2.7.11.11]
18749  Prkacb; protein kinase, cAMP dependent, catalytic, beta [KO:K04345] [EC:2.7.11.11]
14677  Gnai1; G protein subunit alpha i1 [KO:K04630]
14679  Gnai3; G protein subunit alpha i3 [KO:K04630]
14678  Gnai2; G protein subunit alpha i2 [KO:K04630]
14681  Gnao1; guanine nucleotide binding protein, alpha O [KO:K04534]
30955  Pik3cg; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma [KO:K21289] [EC:2.7.1.153]
320207  Pik3r5; phosphoinositide-3-kinase regulatory subunit 5 [KO:K21290]
104709  Pik3r6; phosphoinositide-3-kinase regulatory subunit 5 [KO:K21290]
20779  Src; Rous sarcoma oncogene [KO:K05704] [EC:2.7.10.2]
16519  Kcnj3; potassium inwardly-rectifying channel, subfamily J, member 3 [KO:K04997]
16522  Kcnj6; potassium inwardly-rectifying channel, subfamily J, member 6 [KO:K05000]
16524  Kcnj9; potassium inwardly-rectifying channel, subfamily J, member 9 [KO:K05002]
16521  Kcnj5; potassium inwardly-rectifying channel, subfamily J, member 5 [KO:K04999]
13649  Egfr; epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]
12575  Cdkn1a; cyclin dependent kinase inhibitor 1A [KO:K06625]
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
mmu00590  Arachidonic acid metabolism
mmu04010  MAPK signaling pathway
mmu04020  Calcium signaling pathway
mmu04110  Cell cycle
KO pathway
ko04921   
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