Orexin receptor pathway (Homo sapiens)

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MAPK916MAPK3T202Y2045, 1021MAP2K2S222S216LysosomeRegulation ofMesenchymalStem CellDifferentiationOR /BOTHIncreased Epinephrinesecretion from adrenal medullary cellsOrexin signaling pathwayApoptosis pathway Increased expressionIn anoxia /hypoglycemicastrocytesGenes transcriptionally regulatedby orexin A in GT1-7-OX1 (hypothalamic neurons derived HCRTR1-expressed cell line)Promotesosteogenicdifferentiation& mineralizationmTORC1Potentialregulation ofhypothalamic-pituitary-gonadal axisLysosome v-ATPasePathwayMap LegendIncreasedsurfaceexpression in striatumCatecholaminebiosynthesisin adrenalmedullary cellsIn hypothalamicneuronsNeuro-protectiveeffectCortisolsecretion inAdrenocortical cells (H295R) 6 Orexin-A effect is Gs/Gq/Gi- dependent Orexin-B effect is Gq-dependent Modulation ofKappa opioidreceptor - Gaisignaling Studied for Orexin A and not Orexin B Studied for Orexin B and not Orexin A Studied for both but predominenty Orexin A dependent Studied for both but predominenty Orexin B dependent Studied for both and induced by both Studied with HCRTR1 modulation and not HCRTR2 Studied with HCRTR2 modulation and not HCRTR1 Studied for both but predominenty HCRTR1 dependent Studied for both but predominenty HCRTR2 dependent Studied for both and dependent on both Not studied for both and receptor dependency unknown Based on receptor expression HCRTR1 (predominent) Based on receptor expression HCRTR2 (predominent) Based on receptor expression (may be both) In parvocellular cells of PVN on i.c.v injection Secretion ofosteocalcin in osteoblast-like(ROB) cellsAdenylatecyclase6In pre- anddifferentiated 3T3-L1 adipocytesNPFFR1OPRK126PIK3R1HSD3B2mRNAmRNAModulation ofexcitatory transmission incerebral cortexFMR1NBJARID2PDE11ANSMAFLAMA2OPA1CD24IL4CLEC4CTOXDDX52BTF3HCRTR1MAPK8T185T183MAPK14T180Y1824, 10MAPK1Y187T1854, 5, 10PPARGSLC2A414GlucosemetabolismIn differentiated 3T3-L1 adipocytesAVPCRH3HCRTR2FOS11Potential activationof HPA axis throughCRF and AVP neuronstimulationLIPEPPARGLPLLIPELPLIn subcutaneousHCRTR1 and R2mRNA expressingadipose tissueexplantsGCGReduced pro-glucagonbiosynthesis inglucagon-producingInR1-G9 cellsGlucoseCREB120S133PDPK1S241AKT1S473FOXO1S256PI3KCatalyticMAP2K1S218S222GNASGNAI112, 2212GNAQPKASTARSTARAdreno-corticosteroidogenesisin H295R cellsBGLAPCGALHB1919 Reduced Glycerol release in omental adipose tissue Secretion of LH & FSH gonadotropins in Primary anteriorpituatory cellsCGA19FSHBHCRTR219Increased HCRTR1expression counteractstestosterone-induced nucleartransloaction ofAndrogen Receptorin LnCaP cellsHCRTR19, 19Regulation ofexpression ofHCRTR1/2 inPrimary anteriorpituatory cellsLHFSHMAPK7T218Y220CYP11A1CYP21A2CortisolCYP11B1CYP11B2TriglycerideProduction6HCRTR21966cAMP5, 6666ARRB1HCRTR18Y358Y83ARRB121HCRTR121ARRB2HCRTR1ARRB1ARRB221ARRB2Cell deathin HCRTR1-transfectedCHO-K1 cellsIP34, 5, 8Ca2+1616 Release from ERDAG16, 23PIP2PIP324Ca2+16L-typeCalciumchannels23CNR12THS40Voltage-gatedCa2+ and Na+channelsCCKGlycerolCCKCholecystokininsecretion inSTC-1 cellsGH1GrowthHormonesecretion insomatotropes16Testosterone9, 10Testosteronesecretion intesticular cellsCytochrome C9Cytochrome CCASP7CASP3 Apoptosis in OX1R+ HT29-D4, SK-N-MC, C6 & CHO cell lines21 Sustained HCRTR1-ARRB2 interaction prolonged MAPK1/3 activation in HEK-293T HCRTR1+ cellsPLCD1PRKCEPRKCZHIF1AIncreasedglucoseutilization inhypothalamicneuronsVHLHIF1ALDHAPDK1PDHBActivationof PDH and Suppresionof lactate productionin adipocytesGCGPTPN118PRKCAT638IP1IP2GRIN1GRIN2AGRIN2BGRIA1GRIA2In corticalneuronsGRIA1PRKCDT505PRKCBT641PRKD1S916PRKD3S744S748HCRTR2ARRB1ARRB255HCRTR2ARRB25ARRB155PIK3R2SLC2A4SLC2A4IncreasedGlucose/stimulatedinsulinsecretion inINS-1 cells14ADIPOQAdiponectinsecretion inadipocytesIncreasedglucoseuptake inadipocytesPLD1BMP7BMPR1ABMP7BMPR1ASMAD1S463SMAD5S465PRDM16DYNLT1DYNLT3 Regulation of receptor internalizationHCRTR1Regulation ofexpression ofHCRTR1/2 inleuteal cellsProgesteroneDecreasedProgesteronesecretion byluteal cellsReceptor internalization and recyclingEpinephrinePRKAA123T172IncreasedNeuropeptide Yproduction andregulation offeedingbehaviorCAMKK223NPY23INSReducedglucagonsecretion inglucagon-producingInR1-G9 cells18Pro-survival /anti-apoptoticfunctions inINS-1 cells &BGC-823 gastriccancer cells18HCRTR115Regulation ofexpression ofHCRTR1 inINS-1 cellsInhibition ofosteoblastogenesisand augmentationof bone formationGHRLLEPMTORS2481HepatocyteproliferationRPS6S235S236S240S244RPS6KB1T389EIF4BS422RPS6KA1S380MTORRRAGCGTPDAGLACASP97Pro-survival /anti-apoptotic functions inSGC-7901 cellsEIF4EBP127T46T37Cortisolsecretionin H295Rcells27NFE2L225HMOX1Angiogenesis25NFE2L2HMOX12525CASP318Proliferation /anti-apoptoticfunctions inH295R cellsSLC2A1SLC2A1Increasedglucose uptake inHep3B & HepG2 cellsActivationof PDH andMitochondrialglucoseoxidation inHep3B/G2 cells2-AGMAPK3Y204T202MAPK1T185Y187STAT3S727POMCRepression of satietyPOMC Reduced alpha-MSH release in ARC primary neuronsNRF2 pathwayGNA1122SLC2A1PDHBRUNX1GJA3RARAGLIS1HOMER1LDLRDOK7NPAS4NOCTCLDN4SERP1KCNK3LUZP1NR4A1OPN3PDP1SFPQPER2YARS2TRIM9KLF4CDKN1AHSPA5CCN2MANFNR4A3DUSP4TRA2AOSBPL3TENT5AEGR3EGR1FOSL2EGR2ARCHBEGFMAFFHMGA2JUNBNOGPAPPAGADD45BCXXC5TNCSKILDCLK1ID3FOSLRRC8CIRF5ID1SPP1HES1MYCBHLH40SRFFOSBGLIS2HMGA1ID4KLF10RUNX2ZFP28ZMYM3HAGHLDBPRUNX1T1Sleep deprivationSGK1SGK1 Genes regulated by SGK1 Regulation oflipogenesis and lipolysisLEP14LEP14, 17Regulationof leptinsecretion inadipocytesLEPVEGFAFLT4NOS3PDP1In hypothalamicneuronsIn hypothalamicneuronsPRKCAMAPK1MAPK3Glutamicacid uptakeRegulation of neuron survivalfollowing hypoxicinjurySLC1A2SLC1A2SLC1A2Glutamic acidIn anoxia /hypoglycemicastrocytesTFAMCOX7A1UCP1COX8BPDIO2PPARGCEBPAMitochondrialbiogenesisand brown fatadipogenesisCYPMCa2+Ca2+Ca2+Ca2+Ca2+Ca2+Ca2+PMCYCYECCYPMCYECCYECGlucoseCYECCYECCYECCYECCYECCYPMCYPMCYPMCYPMCYPMCYPMCYPMCYECSRC family8HCRTHCRTHCRTHCRTRUNX2SP7ALPPBGLAPCALCAPPOXCOX2GastroprotectionIncorporationof glucoseto NEFA inadipocytesTriglycerideproduction2-AG Decreased expressionMetaboliteProteinProtein Protein function activation Regulation of gene expression Protein-protein interaction Protein activity inhibition Leads to through known or unknown mechanisms (Multiple colored edges are used to delineate the interconnectivity across crossing edges)Protein Protein family/specific subunits or isozymes not reported in studies Protein phosphosite & residueCYPM Protein transportNUEC Plasma membrane Cytoplasm Nucleus ExtracellularReceptorOrexin AProtein Receptor hypersensitizationNUCYMTCYGNRH126NPVF26IL6CXCL8MMP3MMP13VCAM1ICAM11313SELE13TNFTNF1, 13IL1BIL9IL4IL10NOX4CXCL2Anti-inflammatoryresponse of orexinin IntracerebralhemorrhageProteinXnnn MitochondriaMT Protein cleavagePA2AAPLA2G4A2224Orexin B