KEGG   PATHWAY: hsa04713
hsa04713                    Pathway                                
Circadian entrainment - Homo sapiens (human)
Circadian entrainment is a fundamental property by which the period of the internal biological clock is entrained by recurring exogenous signals, such that the organism's endocrine and behavioral rhythms are synchronized to environmental cues. In mammals, a master clock is located in the suprachiasmatic nuclei (SCN) of the hypothalamus and may synchronize circadian oscillators in peripheral tissues. Light signal is the dominant synchronizer for master SCN clock. Downstream from the retina, glutamate and PACAP are released and trigger the activation of signal transduction cascades, including CamKII and nNOS activity, cAMP- and cGMP-dependent protein kinases, and mitogen-activated protein kinase (MAPK). Of non-photic entrainment, important phase shifting capabilities have been found for melatonin, which inhibits light-induced phase shifts through inhibition of adenylate cyclase (AC). Multiple entrainment pathways converge into CREB regulation. In turn, phosphorylated CREB activates clock gene expression.
Organismal Systems; Environmental adaptation
Pathway map
hsa04713  Circadian entrainment

D02578  Agomelatine (INN)
D02689  Ramelteon (JAN/USAN/INN)
D08170  Melatonin (JAN)
D09388  Tasimelteon (USAN/INN)
Other DBs
GO: 0009649
Homo sapiens (human) [GN:hsa]
2902  GRIN1; glutamate ionotropic receptor NMDA type subunit 1 [KO:K05208]
2903  GRIN2A; glutamate ionotropic receptor NMDA type subunit 2A [KO:K05209]
2904  GRIN2B; glutamate ionotropic receptor NMDA type subunit 2B [KO:K05210]
2905  GRIN2C; glutamate ionotropic receptor NMDA type subunit 2C [KO:K05211]
2906  GRIN2D; glutamate ionotropic receptor NMDA type subunit 2D [KO:K05212]
810  CALML3; calmodulin like 3 [KO:K02183]
805  CALM2; calmodulin 2 [KO:K02183]
808  CALM3; calmodulin 3 [KO:K02183]
801  CALM1; calmodulin 1 [KO:K02183]
163688  CALML6; calmodulin like 6 [KO:K02183]
51806  CALML5; calmodulin like 5 [KO:K02183]
91860  CALML4; calmodulin like 4 [KO:K02183]
815  CAMK2A; calcium/calmodulin dependent protein kinase II alpha [KO:K04515] [EC:]
817  CAMK2D; calcium/calmodulin dependent protein kinase II delta [KO:K04515] [EC:]
816  CAMK2B; calcium/calmodulin dependent protein kinase II beta [KO:K04515] [EC:]
818  CAMK2G; calcium/calmodulin dependent protein kinase II gamma [KO:K04515] [EC:]
4842  NOS1; nitric oxide synthase 1 [KO:K13240] [EC:]
5594  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:]
5595  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:]
9252  RPS6KA5; ribosomal protein S6 kinase A5 [KO:K04445] [EC:]
1385  CREB1; cAMP responsive element binding protein 1 [KO:K05870]
3708  ITPR1; inositol 1,4,5-trisphosphate receptor type 1 [KO:K04958]
3710  ITPR3; inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960]
6261  RYR1; ryanodine receptor 1 [KO:K04961]
6262  RYR2; ryanodine receptor 2 [KO:K04962]
6263  RYR3; ryanodine receptor 3 [KO:K04963]
9722  NOS1AP; nitric oxide synthase 1 adaptor protein [KO:K16513]
51655  RASD1; ras related dexamethasone induced 1 [KO:K07843]
2770  GNAI1; G protein subunit alpha i1 [KO:K04630]
2773  GNAI3; G protein subunit alpha i3 [KO:K04630]
2771  GNAI2; G protein subunit alpha i2 [KO:K04630]
2775  GNAO1; G protein subunit alpha o1 [KO:K04534]
2782  GNB1; G protein subunit beta 1 [KO:K04536]
2783  GNB2; G protein subunit beta 2 [KO:K04537]
2784  GNB3; G protein subunit beta 3 [KO:K07825]
59345  GNB4; G protein subunit beta 4 [KO:K04538]
10681  GNB5; G protein subunit beta 5 [KO:K04539]
54331  GNG2; G protein subunit gamma 2 [KO:K07826]
2785  GNG3; G protein subunit gamma 3 [KO:K04540]
2786  GNG4; G protein subunit gamma 4 [KO:K04541]
2787  GNG5; G protein subunit gamma 5 [KO:K04542]
2788  GNG7; G protein subunit gamma 7 [KO:K04543]
94235  GNG8; G protein subunit gamma 8 [KO:K04544]
2790  GNG10; G protein subunit gamma 10 [KO:K04545]
2791  GNG11; G protein subunit gamma 11 [KO:K04546]
55970  GNG12; G protein subunit gamma 12 [KO:K04347]
51764  GNG13; G protein subunit gamma 13 [KO:K04547]
2792  GNGT1; G protein subunit gamma transducin 1 [KO:K04548]
2793  GNGT2; G protein subunit gamma transducin 2 [KO:K04549]
2890  GRIA1; glutamate ionotropic receptor AMPA type subunit 1 [KO:K05197]
2891  GRIA2; glutamate ionotropic receptor AMPA type subunit 2 [KO:K05198]
2892  GRIA3; glutamate ionotropic receptor AMPA type subunit 3 [KO:K05199]
2893  GRIA4; glutamate ionotropic receptor AMPA type subunit 4 [KO:K05200]
8913  CACNA1G; calcium voltage-gated channel subunit alpha1 G [KO:K04854]
8912  CACNA1H; calcium voltage-gated channel subunit alpha1 H [KO:K04855]
8911  CACNA1I; calcium voltage-gated channel subunit alpha1 I [KO:K04856]
116  ADCYAP1; adenylate cyclase activating polypeptide 1 [KO:K05262]
117  ADCYAP1R1; ADCYAP receptor type I [KO:K04587]
2778  GNAS; GNAS complex locus [KO:K04632]
107  ADCY1; adenylate cyclase 1 [KO:K08041] [EC:]
108  ADCY2; adenylate cyclase 2 [KO:K08042] [EC:]
109  ADCY3; adenylate cyclase 3 [KO:K08043] [EC:]
196883  ADCY4; adenylate cyclase 4 [KO:K08044] [EC:]
111  ADCY5; adenylate cyclase 5 [KO:K08045] [EC:]
112  ADCY6; adenylate cyclase 6 [KO:K08046] [EC:]
113  ADCY7; adenylate cyclase 7 [KO:K08047] [EC:]
114  ADCY8; adenylate cyclase 8 [KO:K08048] [EC:]
115  ADCY9; adenylate cyclase 9 [KO:K08049] [EC:]
55811  ADCY10; adenylate cyclase 10 [KO:K11265] [EC:]
5566  PRKACA; protein kinase cAMP-activated catalytic subunit alpha [KO:K04345] [EC:]
5567  PRKACB; protein kinase cAMP-activated catalytic subunit beta [KO:K04345] [EC:]
5568  PRKACG; protein kinase cAMP-activated catalytic subunit gamma [KO:K04345] [EC:]
2977  GUCY1A2; guanylate cyclase 1 soluble subunit alpha 2 [KO:K12318] [EC:]
2982  GUCY1A1; guanylate cyclase 1 soluble subunit alpha 1 [KO:K12318] [EC:]
2983  GUCY1B1; guanylate cyclase 1 soluble subunit beta 1 [KO:K12319] [EC:]
5592  PRKG1; protein kinase cGMP-dependent 1 [KO:K07376] [EC:]
5593  PRKG2; protein kinase cGMP-dependent 2 [KO:K19477] [EC:]
775  CACNA1C; calcium voltage-gated channel subunit alpha1 C [KO:K04850]
776  CACNA1D; calcium voltage-gated channel subunit alpha1 D [KO:K04851]
4544  MTNR1B; melatonin receptor 1B [KO:K04286]
4543  MTNR1A; melatonin receptor 1A [KO:K04285]
2776  GNAQ; G protein subunit alpha q [KO:K04634]
23236  PLCB1; phospholipase C beta 1 [KO:K05858] [EC:]
5330  PLCB2; phospholipase C beta 2 [KO:K05858] [EC:]
5331  PLCB3; phospholipase C beta 3 [KO:K05858] [EC:]
5332  PLCB4; phospholipase C beta 4 [KO:K05858] [EC:]
5578  PRKCA; protein kinase C alpha [KO:K02677] [EC:]
5579  PRKCB; protein kinase C beta [KO:K19662] [EC:]
5582  PRKCG; protein kinase C gamma [KO:K19663] [EC:]
3760  KCNJ3; potassium inwardly rectifying channel subfamily J member 3 [KO:K04997]
3762  KCNJ5; potassium inwardly rectifying channel subfamily J member 5 [KO:K04999]
3763  KCNJ6; potassium inwardly rectifying channel subfamily J member 6 [KO:K05000]
3765  KCNJ9; potassium inwardly rectifying channel subfamily J member 9 [KO:K05002]
5187  PER1; period circadian regulator 1 [KO:K21944]
8864  PER2; period circadian regulator 2 [KO:K02633]
8863  PER3; period circadian regulator 3 [KO:K21945]
2353  FOS; Fos proto-oncogene, AP-1 transcription factor subunit [KO:K04379]
C00025  L-Glutamate
C00076  Calcium cation
C00165  Diacylglycerol
C00238  Potassium cation
C00533  Nitric oxide
C00575  3',5'-Cyclic AMP
C00942  3',5'-Cyclic GMP
C01330  Sodium cation
C01598  Melatonin
Brown TM, Piggins HD
Electrophysiology of the suprachiasmatic circadian clock.
Prog Neurobiol 82:229-55 (2007)
Dickson L, Finlayson K
VPAC and PAC receptors: From ligands to function.
Pharmacol Ther 121:294-316 (2009)
Golombek DA, Rosenstein RE
Physiology of circadian entrainment.
Physiol Rev 90:1063-102 (2010)
Dubocovich ML, Markowska M
Functional MT1 and MT2 melatonin receptors in mammals.
Endocrine 27:101-10 (2005)
Dubocovich ML, Delagrange P, Krause DN, Sugden D, Cardinali DP, Olcese J
International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, classification, and pharmacology of G protein-coupled melatonin receptors.
Pharmacol Rev 62:343-80 (2010)
Hardeland R
Melatonin: signaling mechanisms of a pleiotropic agent.
Biofactors 35:183-92 (2009)
Golombek DA, Ferreyra GA, Agostino PV, Murad AD, Rubio MF, Pizzio GA, Katz ME, Marpegan L, Bekinschtein TA
From light to genes: moving the hands of the circadian clock.
Front Biosci 8:s285-93 (2003)
Mertens I, Husson SJ, Janssen T, Lindemans M, Schoofs L
PACAP and PDF signaling in the regulation of mammalian and insect circadian rhythms.
Peptides 28:1775-83 (2007)
Kim DY, Choi HJ, Kim JS, Kim YS, Jeong DU, Shin HC, Kim MJ, Han HC, Hong SK, Kim YI
Voltage-gated calcium channels play crucial roles in the glutamate-induced phase shifts of the rat suprachiasmatic circadian clock.
Eur J Neurosci 21:1215-22 (2005)
Agostino PV, Ferreyra GA, Murad AD, Watanabe Y, Golombek DA
Diurnal, circadian and photic regulation of calcium/calmodulin-dependent kinase II and neuronal nitric oxide synthase in the hamster suprachiasmatic nuclei.
Neurochem Int 44:617-25 (2004)
Ferreyra GA, Golombek DA
Rhythmicity of the cGMP-related signal transduction pathway in the mammalian circadian system.
Am J Physiol Regul Integr Comp Physiol 280:R1348-55 (2001)
Butcher GQ, Lee B, Cheng HY, Obrietan K
Light stimulates MSK1 activation in the suprachiasmatic nucleus via a PACAP-ERK/MAP kinase-dependent mechanism.
J Neurosci 25:5305-13 (2005)
Hamada T, Niki T, Ziging P, Sugiyama T, Watanabe S, Mikoshiba K, Ishida N
Differential expression patterns of inositol trisphosphate receptor types 1 and 3 in the rat suprachiasmatic nucleus.
Brain Res 838:131-5 (1999)
Diaz-Munoz M, Dent MA, Granados-Fuentes D, Hall AC, Hernandez-Cruz A, Harrington ME, Aguilar-Roblero R
Circadian modulation of the ryanodine receptor type 2 in the SCN of rodents.
Neuroreport 10:481-6 (1999)
Fang M, Jaffrey SR, Sawa A, Ye K, Luo X, Snyder SH
Dexras1: a G protein specifically coupled to neuronal nitric oxide synthase via CAPON.
Neuron 28:183-93 (2000)
Takahashi H, Umeda N, Tsutsumi Y, Fukumura R, Ohkaze H, Sujino M, van der Horst G, Yasui A, Inouye ST, Fujimori A, Ohhata T, Araki R, Abe M
Mouse dexamethasone-induced RAS protein 1 gene is expressed in a circadian rhythmic manner in the suprachiasmatic nucleus.
Brain Res Mol Brain Res 110:1-6 (2003)
Cheng HY, Dziema H, Papp J, Mathur DP, Koletar M, Ralph MR, Penninger JM, Obrietan K
The molecular gatekeeper Dexras1 sculpts the photic responsiveness of the mammalian circadian clock.
J Neurosci 26:12984-95 (2006)
hsa04010  MAPK signaling pathway
hsa04710  Circadian rhythm
KO pathway

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