KEGG   PATHWAY: ngi04921
Entry
ngi04921                    Pathway                                
Name
Oxytocin signaling pathway - Nannospalax galili (Upper Galilee mountains blind mole rat)
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
ngi04921  Oxytocin signaling pathway
ngi04921

Organism
Nannospalax galili (Upper Galilee mountains blind mole rat) [GN:ngi]
Gene
103751127  oxytocin-neurophysin 1 [KO:K05243]
103751126  Avp; arginine vasopressin [KO:K05243]
103751407  Oxtr; oxytocin receptor [KO:K04229]
103734421  Gnaq; guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
103751075  Hras; HRas proto-oncogene, GTPase [KO:K02833]
103736717  Kras; KRAS proto-oncogene, GTPase [KO:K07827]
103734938  Nras; neuroblastoma RAS viral oncogene homolog [KO:K07828]
103751450  Raf1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:2.7.11.1]
103736801  Map2k1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
103737276  Map2k2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
103741442  Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
103726390  Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
103744946  Pla2g4d; phospholipase A2 group IVD [KO:K16342] [EC:3.1.1.4]
103744945  Pla2g4e; phospholipase A2 group IVE [KO:K16342] [EC:3.1.1.4]
103744942  Pla2g4b; phospholipase A2 group IVB [KO:K16342] [EC:3.1.1.4]
103744947  Pla2g4f; phospholipase A2 group IVF [KO:K16342] [EC:3.1.1.4]
103726649  Pla2g4a; phospholipase A2 group IVA [KO:K16342] [EC:3.1.1.4]
103732429  Pla2g4c; phospholipase A2 group IVC [KO:K16342] [EC:3.1.1.4]
103726651  Ptgs2; prostaglandin-endoperoxide synthase 2 [KO:K11987] [EC:1.14.99.1]
103736811  Map2k5; mitogen-activated protein kinase kinase 5 [KO:K04463] [EC:2.7.12.2]
103728439  Mapk7; mitogen-activated protein kinase 7 [KO:K04464] [EC:2.7.11.24]
103737138  Jun; Jun proto-oncogene, AP-1 transcription factor subunit [KO:K04448]
103747342  Fos; Fos proto-oncogene, AP-1 transcription factor subunit [KO:K04379]
103739124  Mef2c; myocyte enhancer factor 2C [KO:K04454]
103751498  Ccnd1; cyclin D1 [KO:K04503]
103741629  Elk1; ELK1, ETS transcription factor [KO:K04375]
103750787  Ryr1; ryanodine receptor 1 [KO:K04961]
103743548  ryanodine receptor 2-like [KO:K04962]
103740528  Ryr3; ryanodine receptor 3 [KO:K04963]
103728882  Cd38; CD38 molecule [KO:K01242] [EC:3.2.2.6 2.4.99.20]
103729355  Trpm2; transient receptor potential cation channel subfamily M member 2 [KO:K04977] [EC:3.6.1.13]
103748279  Kcnj2; potassium voltage-gated channel subfamily J member 2 [KO:K04996]
103724820  Kcnj12; ATP-sensitive inward rectifier potassium channel 12 [KO:K05005]
103748587  Kcnj4; potassium voltage-gated channel subfamily J member 4 [KO:K04998]
103743613  Kcnj14; potassium voltage-gated channel subfamily J member 14 [KO:K05007]
103735195  Plcb1; phospholipase C beta 1 [KO:K05858] [EC:3.1.4.11]
103738797  Plcb3; phospholipase C beta 3 [KO:K05858] [EC:3.1.4.11]
103741502  Plcb2; phospholipase C beta 2 [KO:K05858] [EC:3.1.4.11]
103742202  Prkca; protein kinase C alpha [KO:K02677] [EC:2.7.11.13]
103746928  Prkcb; protein kinase C beta [KO:K19662] [EC:2.7.11.13]
103729666  Prkcg; protein kinase C gamma [KO:K19663] [EC:2.7.11.13]
103742746  Eef2k; eukaryotic elongation factor 2 kinase [KO:K08292] [EC:2.7.11.20]
103737272  Eef2; eukaryotic translation elongation factor 2 [KO:K03234]
103739378  Cacna1c; calcium voltage-gated channel subunit alpha1 C [KO:K04850]
103749025  Cacna1d; calcium voltage-gated channel subunit alpha1 D [KO:K04851]
103741673  Cacna1f; calcium voltage-gated channel subunit alpha1 F [KO:K04853]
103731814  Cacna1s; calcium voltage-gated channel subunit alpha1 S [KO:K04857]
103743810  Cacnb1; calcium voltage-gated channel auxiliary subunit beta 1 [KO:K04862]
103726514  Cacnb2; calcium voltage-gated channel auxiliary subunit beta 2 [KO:K04863]
103750559  Cacnb3; calcium voltage-gated channel auxiliary subunit beta 3 [KO:K04864]
103738122  Cacnb4; calcium voltage-gated channel auxiliary subunit beta 4 [KO:K04865]
103730725  Cacna2d1; calcium voltage-gated channel auxiliary subunit alpha2delta 1 [KO:K04858]
103750148  Cacna2d2; calcium voltage-gated channel auxiliary subunit alpha2delta 2 [KO:K04859]
103749031  Cacna2d3; calcium voltage-gated channel auxiliary subunit alpha2delta 3 [KO:K04860]
103739384  Cacna2d4; calcium voltage-gated channel auxiliary subunit alpha2delta 4 [KO:K04861]
103742198  Cacng1; calcium voltage-gated channel auxiliary subunit gamma 1 [KO:K04866]
103748628  Cacng2; calcium voltage-gated channel auxiliary subunit gamma 2 [KO:K04867]
103746927  Cacng3; calcium voltage-gated channel auxiliary subunit gamma 3 [KO:K04868]
103742200  Cacng4; calcium voltage-gated channel auxiliary subunit gamma 4 [KO:K04869]
103742201  Cacng5; calcium voltage-gated channel auxiliary subunit gamma 5 [KO:K04870]
103729669  Cacng6; calcium voltage-gated channel auxiliary subunit gamma 6 [KO:K04871]
103729667  Cacng7; calcium voltage-gated channel auxiliary subunit gamma 7 [KO:K04872]
103729702  Cacng8; calcium voltage-gated channel auxiliary subunit gamma 8 [KO:K04873]
103751203  Itpr1; inositol 1,4,5-trisphosphate receptor type 1 [KO:K04958]
103739696  Itpr3; inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960]
103737134  Calml3; calmodulin like 3 [KO:K02183]
103737133  Calml5; calmodulin like 5 [KO:K02183]
103749800  Calml6; calmodulin like 6 [KO:K02183]
103724616  Calm1; calmodulin 1 [KO:K02183]
103724738  Calm3; calmodulin 3 [KO:K02183]
103725745  Calm2; calmodulin 2 [KO:K02183]
103729208  calmodulin-alpha-like [KO:K02183]
103736816  Calml4; calmodulin like 4 [KO:K02183]
103736944  Ppp3cb; protein phosphatase 3 catalytic subunit beta [KO:K04348] [EC:3.1.3.16]
103747869  Ppp3cc; protein phosphatase 3 catalytic subunit gamma [KO:K04348] [EC:3.1.3.16]
103728037  Ppp3ca; protein phosphatase 3 catalytic subunit alpha [KO:K04348] [EC:3.1.3.16]
103734750  Ppp3r1; protein phosphatase 3 regulatory subunit B, alpha [KO:K06268]
103749104  Ppp3r2; calcineurin subunit B type 2 [KO:K06268]
103748128  Nfatc1; nuclear factor of activated T-cells 1 [KO:K04446]
103735763  Nfatc2; nuclear factor of activated T-cells 2 [KO:K17332]
103734978  Nfatc3; nuclear factor of activated T-cells 3 [KO:K17333]
103739410  Nfatc4; nuclear factor of activated T-cells 4 [KO:K17334]
103736710  Rgs2; regulator of G-protein signaling 2 [KO:K18154]
103736433  Rcan1; regulator of calcineurin 1 [KO:K17901]
103739072  Camkk2; calcium/calmodulin dependent protein kinase kinase 2 [KO:K07359] [EC:2.7.11.17]
103734094  Prkaa2; protein kinase AMP-activated catalytic subunit alpha 2 [KO:K07198] [EC:2.7.11.31]
103741338  Prkaa1; protein kinase AMP-activated catalytic subunit alpha 1 [KO:K07198] [EC:2.7.11.31]
103726789  Prkab1; protein kinase AMP-activated non-catalytic subunit beta 1 [KO:K07199]
103731998  Prkab2; protein kinase AMP-activated non-catalytic subunit beta 2 [KO:K07199]
103745323  Prkag2; protein kinase AMP-activated non-catalytic subunit gamma 2 [KO:K07200]
103750569  Prkag1; protein kinase AMP-activated non-catalytic subunit gamma 1 [KO:K07200]
103727728  Prkag3; protein kinase AMP-activated non-catalytic subunit gamma 3 [KO:K07200]
103746367  Camk1d; calcium/calmodulin dependent protein kinase ID [KO:K08794] [EC:2.7.11.17]
103751418  Camk1; calcium/calmodulin dependent protein kinase I [KO:K08794] [EC:2.7.11.17]
103727073  Camk1g; calcium/calmodulin dependent protein kinase IG [KO:K08794] [EC:2.7.11.17]
103736933  Camk2g; calcium/calmodulin dependent protein kinase II gamma [KO:K04515] [EC:2.7.11.17]
103734983  Camk2b; calcium/calmodulin dependent protein kinase II beta [KO:K04515] [EC:2.7.11.17]
103743264  Camk2d; calcium/calmodulin dependent protein kinase II delta [KO:K04515] [EC:2.7.11.17]
103747079  Camk2a; calcium/calmodulin dependent protein kinase II alpha [KO:K04515] [EC:2.7.11.17]
103752296  Camk4; calcium/calmodulin dependent protein kinase IV [KO:K05869] [EC:2.7.11.17]
103745303  Nos3; nitric oxide synthase 3 [KO:K13242] [EC:1.14.13.39]
103751001  Gucy1a3; guanylate cyclase 1 soluble subunit alpha [KO:K12318] [EC:4.6.1.2]
103731324  Gucy1a2; guanylate cyclase 1 soluble subunit alpha 2 [KO:K12318] [EC:4.6.1.2]
103751002  Gucy1b3; guanylate cyclase 1 soluble subunit beta [KO:K12319] [EC:4.6.1.2]
103727194  guanylate cyclase soluble subunit beta-2-like [KO:K12319] [EC:4.6.1.2]
103747472  Nppa; natriuretic peptide A [KO:K12334]
103751781  Npr1; natriuretic peptide receptor 1 [KO:K12323] [EC:4.6.1.2]
103741534  Npr2; natriuretic peptide receptor 2 [KO:K12324] [EC:4.6.1.2]
103731078  Mylk2; myosin light chain kinase 2 [KO:K00907] [EC:2.7.11.18]
103737011  Mylk4; myosin light chain kinase family member 4 [KO:K00907] [EC:2.7.11.18]
103741992  Mylk; myosin light chain kinase [KO:K00907] [EC:2.7.11.18]
103745443  Mylk3; myosin light chain kinase 3 [KO:K00907] [EC:2.7.11.18]
103746506  Myl6b; myosin light chain 6B [KO:K12751]
103746507  Myl6; myosin light chain 6 [KO:K12751]
103740213  Myl9; myosin light chain 9 [KO:K12755]
103748521  myosin regulatory light polypeptide 9 [KO:K12755]
103730387  Actg1; actin gamma 1 [KO:K05692]
103748659  Actb; actin beta [KO:K05692]
103743359  transforming protein RhoA-like [KO:K04513]
103750189  Rhoa; ras homolog family member A [KO:K04513]
103728977  Rock1; Rho associated coiled-coil containing protein kinase 1 [KO:K04514] [EC:2.7.11.1]
103747607  Rock2; Rho associated coiled-coil containing protein kinase 2 [KO:K17388] [EC:2.7.11.1]
103739088  Ppp1cc; protein phosphatase 1 catalytic subunit gamma [KO:K06269] [EC:3.1.3.16]
103725581  Ppp1ca; protein phosphatase 1 catalytic subunit alpha [KO:K06269] [EC:3.1.3.16]
103730228  Ppp1cb; protein phosphatase 1 catalytic subunit beta [KO:K06269] [EC:3.1.3.16]
103749250  Ppp1r12a; protein phosphatase 1 regulatory subunit 12A [KO:K06270]
103731836  Ppp1r12b; protein phosphatase 1 regulatory subunit 12B [KO:K12329]
103744825  Ppp1r12c; protein phosphatase 1 regulatory subunit 12C [KO:K17457]
103741475  Gnas; GNAS complex locus [KO:K04632]
103741466  neuroendocrine secretory protein 55 [KO:K04632]
103741433  Adcy1; adenylate cyclase 1 [KO:K08041] [EC:4.6.1.1]
103735350  Adcy2; adenylate cyclase 2 [KO:K08042] [EC:4.6.1.1]
103746460  Adcy3; adenylate cyclase 3 [KO:K08043] [EC:4.6.1.1]
103739411  Adcy4; adenylate cyclase 4 [KO:K08044] [EC:4.6.1.1]
103741989  Adcy5; adenylate cyclase 5 [KO:K08045] [EC:4.6.1.1]
103750558  Adcy6; adenylate cyclase 6 [KO:K08046] [EC:4.6.1.1]
103730120  Adcy7; adenylate cyclase 7 [KO:K08047] [EC:4.6.1.1]
103743923  Adcy8; adenylate cyclase 8 [KO:K08048] [EC:4.6.1.1]
103744458  Adcy9; adenylate cyclase 9 [KO:K08049] [EC:4.6.1.1]
103751850  Prkaca; protein kinase cAMP-activated catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
103728095  Prkacb; protein kinase cAMP-activated catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
103747835  Gnai3; G protein subunit alpha i3 [KO:K04630]
103750163  Gnai2; G protein subunit alpha i2 [KO:K04630]
103724646  guanine nucleotide-binding protein G(i) subunit alpha-2-like [KO:K04630]
103732220  Gnai1; G protein subunit alpha i1 [KO:K04630]
103749858  Gnao1; G protein subunit alpha o1 [KO:K04534]
103732179  Pik3cg; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma [KO:K21289] [EC:2.7.1.153]
103752079  Pik3r5; phosphoinositide-3-kinase regulatory subunit 5 [KO:K21290]
103752080  Pik3r6; phosphoinositide-3-kinase regulatory subunit 6 [KO:K21290]
103752029  Src; SRC proto-oncogene, non-receptor tyrosine kinase [KO:K05704] [EC:2.7.10.2]
103733966  Kcnj3; potassium voltage-gated channel subfamily J member 3 [KO:K04997]
103750100  Kcnj6; potassium voltage-gated channel subfamily J member 6 [KO:K05000]
103740232  Kcnj9; potassium voltage-gated channel subfamily J member 9 [KO:K05002]
103740685  Kcnj5; potassium voltage-gated channel subfamily J member 5 [KO:K04999]
103748852  epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]
103739652  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
ngi00590  Arachidonic acid metabolism
ngi04010  MAPK signaling pathway
ngi04020  Calcium signaling pathway
ngi04110  Cell cycle
KO pathway
ko04921   
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