KEGG   PATHWAY: ocu04921
Entry
ocu04921                    Pathway                                
Name
Oxytocin signaling pathway - Oryctolagus cuniculus (rabbit)
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
ocu04921  Oxytocin signaling pathway
ocu04921

Organism
Oryctolagus cuniculus (rabbit) [GN:ocu]
Gene
100343798  oxytocin [KO:K05243]
100008670  OXTR; oxytocin receptor [KO:K04229]
100340719  guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
127486605  GTPase HRas isoform X1 [KO:K02833]
100347487  GTPase KRas isoform X1 [KO:K07827]
127489236  GTPase KRas-like [KO:K07827]
100344241  GTPase NRas [KO:K07828]
100347407  RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
100009316  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
127489461  LOW QUALITY PROTEIN: dual specificity mitogen-activated protein kinase kinase 1-like [KO:K04368] [EC:2.7.12.2]
100347345  mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
100348561  mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
100533118  PLA2G4B; cytosolic phospholipase A2 beta [KO:K16342] [EC:3.1.1.4]
100340517  cytosolic phospholipase A2 zeta isoform X1 [KO:K16342] [EC:3.1.1.4]
100340775  cytosolic phospholipase A2 delta isoform X2 [KO:K16342] [EC:3.1.1.4]
100341033  PLA2G4E; cytosolic phospholipase A2 epsilon [KO:K16342] [EC:3.1.1.4]
100008748  PLA2G4A; cytosolic phospholipase A2 [KO:K16342] [EC:3.1.1.4]
100341237  cytosolic phospholipase A2 gamma isoform X1 [KO:K16342] [EC:3.1.1.4]
100009248  PTGS2; prostaglandin G/H synthase 2 precursor [KO:K11987] [EC:1.14.99.1]
100358715  dual specificity mitogen-activated protein kinase kinase 5 isoform X1 [KO:K04463] [EC:2.7.12.2]
100338535  mitogen-activated protein kinase 7 isoform X2 [KO:K04464] [EC:2.7.11.24]
100008856  JUN; transcription factor Jun [KO:K04448]
100338345  protein c-Fos [KO:K04379]
100345167  myocyte-specific enhancer factor 2C isoform X1 [KO:K04454]
100340952  ETS domain-containing protein Elk-1 [KO:K04375]
100009540  RYR1; ryanodine receptor 1 [KO:K04961]
100009536  RYR2; ryanodine receptor 2 [KO:K04962]
100009545  RYR3; ryanodine receptor 3 [KO:K04963]
100009409  CD38; ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 [KO:K01242] [EC:3.2.2.6 2.4.99.20]
103347481  transient receptor potential cation channel subfamily M member 2 isoform X1 [KO:K04977] [EC:3.6.1.13]
100008987  KCNJ2; inward rectifier potassium channel 2 [KO:K04996]
100008860  IRK2; IRK2 inward rectifier potassium channel [KO:K05005]
100338640  inward rectifier potassium channel 4 [KO:K04998]
100348877  LOW QUALITY PROTEIN: ATP-sensitive inward rectifier potassium channel 14 [KO:K05007]
100348672  1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X4 [KO:K05858] [EC:3.1.4.11]
100350395  1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
100341512  1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X2 [KO:K05858] [EC:3.1.4.11]
103347536  1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
100037720  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
100037719  PRKCB; protein kinase C beta type isoform I [KO:K19662] [EC:2.7.11.13]
100009102  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
100347896  eukaryotic elongation factor 2 kinase isoform X1 [KO:K08292] [EC:2.7.11.20]
127485698  elongation factor 2 [KO:K03234]
100101555  CACNA1C; voltage-dependent L-type calcium channel subunit alpha-1C [KO:K04850]
100327259  CACNA1D; voltage-dependent L-type calcium channel subunit alpha-1D isoform X1 [KO:K04851]
100357261  voltage-dependent L-type calcium channel subunit alpha-1F [KO:K04853]
100009585  CACNA1S; voltage-dependent L-type calcium channel subunit alpha-1S [KO:K04857]
100009109  CACNB1; voltage-dependent L-type calcium channel subunit beta-1 [KO:K04862]
100009277  CACNB2; voltage-dependent L-type calcium channel subunit beta-2 [KO:K04863]
100009402  CACNB3; voltage-dependent L-type calcium channel subunit beta-3 [KO:K04864]
100344224  voltage-dependent L-type calcium channel subunit beta-4 isoform X1 [KO:K04865]
100009105  CACNA2D1; voltage-dependent calcium channel subunit alpha-2/delta-1 preproprotein [KO:K04858]
100340494  voltage-dependent calcium channel subunit alpha-2/delta-2 isoform X7 [KO:K04859]
100351327  voltage-dependent calcium channel subunit alpha-2/delta-3 isoform X1 [KO:K04860]
100354108  voltage-dependent calcium channel subunit alpha-2/delta-4 [KO:K04861]
100009263  CACNG1; voltage-dependent calcium channel gamma-1 subunit [KO:K04866]
100350483  voltage-dependent calcium channel gamma-2 subunit [KO:K04867]
100350075  voltage-dependent calcium channel gamma-3 subunit [KO:K04868]
100338772  voltage-dependent calcium channel gamma-4 subunit [KO:K04869]
100339021  voltage-dependent calcium channel gamma-5 subunit [KO:K04870]
100351877  voltage-dependent calcium channel gamma-6 subunit isoform X1 [KO:K04871]
100328774  CACNG7; voltage-dependent calcium channel gamma-7 subunit [KO:K04872]
103346112  voltage-dependent calcium channel gamma-8 subunit [KO:K04873]
100009505  inositol 1,4,5-trisphosphate receptor type 1 [KO:K04958]
100356806  inositol 1,4,5-trisphosphate receptor type 2 isoform X1 [KO:K04959]
100008939  inositol 1,4,5-trisphosphate receptor type 3 isoform X1 [KO:K04960]
103345165  LOW QUALITY PROTEIN: calmodulin-like protein 3 [KO:K02183]
100347856  calmodulin-like protein 3 [KO:K02183]
100354905  calmodulin-3 [KO:K02183]
100352392  CALM2; calmodulin [KO:K02183]
100350107  calmodulin-1 [KO:K02183]
100345526  calmodulin-like protein 4 isoform X1 [KO:K02183]
100356245  serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform isoform X1 [KO:K04348] [EC:3.1.3.16]
100009423  PPP3CA; protein phosphatase 3 catalytic subunit alpha [KO:K04348] [EC:3.1.3.16]
100009487  PPP3CB; serine/threonine-protein phosphatase 2B catalytic subunit beta isoform [KO:K04348] [EC:3.1.3.16]
100344533  calcineurin subunit B type 2 [KO:K06268]
100352378  nuclear factor of activated T-cells, cytoplasmic 1 [KO:K04446]
100353824  nuclear factor of activated T-cells, cytoplasmic 2 isoform X3 [KO:K17332]
100008859  nuclear factor of activated T-cells, cytoplasmic 3 isoform X2 [KO:K17333]
100347003  nuclear factor of activated T-cells, cytoplasmic 4 isoform X2 [KO:K17334]
100345200  regulator of G-protein signaling 2 [KO:K18154]
100349268  regulator of G-protein signaling 2 [KO:K18154]
127486775  regulator of G-protein signaling 2-like [KO:K18154]
100339855  calcipressin-1 isoform X2 [KO:K17901]
100350689  calcium/calmodulin-dependent protein kinase kinase 2 isoform X1 [KO:K07359] [EC:2.7.11.17]
127488422  calcium/calmodulin-dependent protein kinase kinase 2 isoform X1 [KO:K07359] [EC:2.7.11.17]
100340670  5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform X2 [KO:K07198] [EC:2.7.11.31]
100358166  5'-AMP-activated protein kinase catalytic subunit alpha-1 [KO:K07198] [EC:2.7.11.31]
100348780  5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
100340412  5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
100353180  5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
100356542  5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
100352581  5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
100343415  calcium/calmodulin-dependent protein kinase type 1D isoform X1 [KO:K08794] [EC:2.7.11.17]
100343158  calcium/calmodulin-dependent protein kinase type 1G isoform X1 [KO:K08794] [EC:2.7.11.17]
100351552  calcium/calmodulin-dependent protein kinase type 1 isoform X1 [KO:K08794] [EC:2.7.11.17]
100342451  calcium/calmodulin-dependent protein kinase type II subunit beta isoform X1 [KO:K04515] [EC:2.7.11.17]
100341507  calcium/calmodulin-dependent protein kinase type II subunit alpha isoform X1 [KO:K04515] [EC:2.7.11.17]
100101557  CAMK2D; calcium/calmodulin-dependent protein kinase type II subunit delta [KO:K04515] [EC:2.7.11.17]
100101556  CAMK2G; calcium/calmodulin-dependent protein kinase type II subunit gamma [KO:K04515] [EC:2.7.11.17]
103345118  calcium/calmodulin-dependent protein kinase type IV isoform X1 [KO:K05869] [EC:2.7.11.17]
100009498  NOS3; nitric oxide synthase, endothelial [KO:K13242] [EC:1.14.13.39]
127493711  nitric oxide synthase, endothelial isoform X1 [KO:K13242] [EC:1.14.13.39]
100350099  GUCY1A1; guanylate cyclase soluble subunit alpha-1 isoform X1 [KO:K12318] [EC:4.6.1.2]
100357621  guanylate cyclase soluble subunit alpha-2 [KO:K12318] [EC:4.6.1.2]
100349851  GUCY1B1; guanylate cyclase soluble subunit beta-1 [KO:K12319] [EC:4.6.1.2]
100009087  NPPA; natriuretic peptides A precursor [KO:K12334]
100343663  atrial natriuretic peptide receptor 1 [KO:K12323] [EC:4.6.1.2]
100356598  atrial natriuretic peptide receptor 2 isoform X1 [KO:K12324] [EC:4.6.1.2]
100009051  MYLK2; myosin light chain kinase 2, skeletal/cardiac muscle [KO:K00907] [EC:2.7.11.18]
100353972  myosin light chain kinase family member 4 isoform X1 [KO:K00907] [EC:2.7.11.18]
100348694  myosin light chain kinase 3 isoform X1 [KO:K00907] [EC:2.7.11.18]
127493971  myosin light chain kinase, smooth muscle [KO:K00907] [EC:2.7.11.18]
100355039  myosin light polypeptide 6-like [KO:K12751]
103348296  myosin light chain 6B isoform X1 [KO:K12751]
100349824  myosin light polypeptide 6 isoform X3 [KO:K12751]
108176653  myosin light polypeptide 6 isoform X1 [KO:K12751]
127487399  myosin light chain 6B isoform X1 [KO:K12751]
100343384  myosin regulatory light polypeptide 9 [KO:K12755]
100008822  actin, cytoplasmic 1 [KO:K05692]
100009272  ACTB; actin, cytoplasmic 1 [KO:K05692]
100341037  LOW QUALITY PROTEIN: actin, cytoplasmic 2-like [KO:K05692]
100356250  transforming protein RhoA [KO:K04513]
100348967  transforming protein RhoA-like [KO:K04513]
100340661  transforming protein RhoA [KO:K04513]
100346856  LOW QUALITY PROTEIN: transforming protein RhoA [KO:K04513]
100343368  transforming protein RhoA-like [KO:K04513]
100343680  transforming protein RhoA-like [KO:K04513]
127489660  transforming protein RhoA-like [KO:K04513]
100009220  ROCK1; rho-associated protein kinase 1 [KO:K04514] [EC:2.7.11.1]
100346837  rho-associated protein kinase 2 isoform X1 [KO:K17388] [EC:2.7.11.1]
100009587  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
100009298  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
100353054  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
100350558  protein phosphatase 1 regulatory subunit 12A isoform X1 [KO:K06270]
100356902  protein phosphatase 1 regulatory subunit 12B isoform X8 [KO:K12329]
100008904  guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas isoform X1 [KO:K04632]
100346323  neuroendocrine secretory protein 55 [KO:K04632]
103347035  adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
100009201  adenylate cyclase type 2 isoform X1 [KO:K08042] [EC:4.6.1.1]
100343958  adenylate cyclase type 3 isoform X1 [KO:K08043] [EC:4.6.1.1]
100346742  adenylate cyclase type 4 isoform X1 [KO:K08044] [EC:4.6.1.1]
100009315  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
100354934  adenylate cyclase type 6 isoform X8 [KO:K08046] [EC:4.6.1.1]
100357357  adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:4.6.1.1]
100337882  adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:4.6.1.1]
100340877  adenylate cyclase type 9 isoform X1 [KO:K08049] [EC:4.6.1.1]
100008815  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
100342212  cAMP-dependent protein kinase catalytic subunit beta isoform X3 [KO:K04345] [EC:2.7.11.11]
100338391  guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
100359147  guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
100339066  guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
100342283  guanine nucleotide-binding protein G(o) subunit alpha isoform X1 [KO:K04534]
100344144  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform [KO:K21289] [EC:2.7.1.153]
100337757  phosphoinositide 3-kinase regulatory subunit 5 isoform X1 [KO:K21290]
100340526  LOW QUALITY PROTEIN: phosphoinositide 3-kinase regulatory subunit 6 [KO:K21290]
100341599  proto-oncogene tyrosine-protein kinase Src isoform X1 [KO:K05704] [EC:2.7.10.2]
100009366  G protein-activated inward rectifier potassium channel 1 [KO:K04997]
100008865  G protein-activated inward rectifier potassium channel 2 [KO:K05000]
100345513  G protein-activated inward rectifier potassium channel 3 [KO:K05002]
100352473  G protein-activated inward rectifier potassium channel 4 [KO:K04999]
100008806  epidermal growth factor receptor isoform X1 [KO:K04361] [EC:2.7.10.1]
100348489  cyclin-dependent kinase inhibitor 1 [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
ocu00590  Arachidonic acid metabolism
ocu04010  MAPK signaling pathway
ocu04020  Calcium signaling pathway
ocu04110  Cell cycle
KO pathway
ko04921   
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