Orexin receptor pathway (Homo sapiens)

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256LysosomeRegulation ofMesenchymalStem CellDifferentiationOR /BOTHIncreased Epinephrinesecretion from adrenal medullary cellsApoptosis 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-ATPasePathwayLegendIncreasedsurfaceexpression in striatumCatecholaminebiosynthesisin adrenalmedullary cellsIn hypothalamicneuronsNeuro-protectiveeffectCortisolsecretion inAdrenocortical cells (H295R) 1 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) cellsAdenylatecyclaseIn pre- anddifferentiated 3T3-L1 adipocytes1mRNAmRNAModulation ofexcitatory transmission incerebral cortexIn differentiated 3T3-L1 adipocytesPotential activationof HPA axis throughCRF and AVP neuronstimulationIn subcutaneousHCRTR1 and R2mRNA expressingadipose tissueexplantsReduced pro-glucagonbiosynthesis inglucagon-producingInR1-G9 cellsAdreno-corticosteroidogenesisin H295R cells Reduced Glycerol release in omental adipose tissue Secretion of LH & FSH gonadotropins in Primary anteriorpituatory cellsIncreased HCRTR1expression counteractstestosterone-induced nucleartransloaction ofAndrogen Receptorin LnCaP cellsRegulation ofexpression ofHCRTR1/2 inPrimary anteriorpituatory cellsLHFSHProduction1111116Cell deathin HCRTR1-transfectedCHO-K1 cells25 Release from ER10, 252625Cholecystokininsecretion inSTC-1 cellsGrowthHormonesecretion insomatotropesTestosteronesecretion intesticular cells16 Apoptosis in OX1R+ HT29-D4, SK-N-MC, C6 & CHO cell lines6 Sustained HCRTR1-ARRB2 interaction prolonged MAPK1/3 activation in HEK-293T HCRTR1+ cellsIncreasedglucoseutilization inhypothalamicneuronsActivationof PDH and Suppresionof lactate productionin adipocytesIn corticalneurons27IncreasedGlucose/stimulatedinsulinsecretion inINS-1 cellsAdiponectinsecretion inadipocytesIncreasedglucoseuptake inadipocytes Regulation of receptor internalizationRegulation ofexpression ofHCRTR1/2 inleuteal cellsDecreasedProgesteronesecretion byluteal cellsReceptor internalization and recyclingIncreasedNeuropeptide Yproduction andregulation offeedingbehaviorReducedglucagonsecretion inglucagon-producingInR1-G9 cellsPro-survival /anti-apoptoticfunctions inINS-1 cells &BGC-823 gastriccancer cells3Regulation ofexpression ofHCRTR1 inINS-1 cellsInhibition ofosteoblastogenesisand augmentationof bone formationHepatocyteproliferationPro-survival /anti-apoptotic functions inSGC-7901 cellsCortisolsecretionin H295Rcells8AngiogenesisProliferation /anti-apoptoticfunctions inH295R cellsIncreasedglucose uptake inHep3B & HepG2 cellsActivationof PDH andMitochondrialglucoseoxidation inHep3B/G2 cellsRepression of satiety Reduced alpha-MSH release in ARC primary neuronsNRF2 pathwaySleep deprivation Genes regulated by SGK1 Regulation oflipogenesis and lipolysisRegulationof leptinsecretion inadipocytesIn hypothalamicneuronsIn hypothalamicneuronsRegulation of neuron survivalfollowing hypoxicinjuryIn anoxia /hypoglycemicastrocytesMitochondrialbiogenesisand brown fatadipogenesisCYPMPMCYCYECCYPMCYECCYECCYECCYECCYECCYECCYECCYPMCYPMCYPMCYPMCYPMCYPMCYPMCYECSRC family18GastroprotectionIncorporationof glucoseto NEFA inadipocytesTriglycerideproduction 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 hypersensitizationNUCYMTCYAnti-inflammatoryresponse of orexinin IntracerebralhemorrhageProteinXnnn MitochondriaMT Protein cleavage26Orexin B2-AGMAPK9MAPK32, 27T202Y204MAP2K2NPFFR1S222S216OPRK112PIK3R1HSD3B2FMR1NBJARID2PDE11ANSMAFLAMA2OPA1CD24IL4CLEC4CTOXDDX52BTF3HCRTR1MAPK8T185MAPK14T183T180MAPK1Y1822, 11PPARGY187T1852, 11, 27SLC2A4Glucosemetabolism17AVPCRH23HCRTR2FOS14LIPEPPARGLPLLIPELPLGCGGlucoseCREB14PDPK1S133AKT1S241FOXO1S473PI3KCatalyticS256MAP2K1S218GNASS2229, 13GNAI1GNAQ9PKASTARSTARBGLAPCGALHB2020CGA20FSHB20HCRTR2HCRTR116, 20MAPK7T218Y220CYP11A1CYP21A2CortisolCYP11B1CYP11B2TriglycerideHCRTR220cAMP1, 27ARRB1HCRTR118Y358Y83ARRB1HCRTR16ARRB2HCRTR1ARRB1ARRB2ARRB26IP311, 18, 27Ca2+DAG25PIP2PIP3Ca2+L-typeCalciumchannels10CNR121THVoltage-gatedCa2+ and Na+channelsS40CCKGlycerolCCKGH1Testosterone252, 16Cytochrome CCytochrome CCASP7CASP3PLCD1PRKCEPRKCZHIF1AVHLHIF1ALDHAPDK1PDHBGCGPTPN11PRKCA18IP1T638IP2GRIN1GRIN2AGRIN2BGRIA1GRIA2GRIA1PRKCDT505PRKCBPRKD1T641S916PRKD3S744S748HCRTR2ARRB1ARRB22727HCRTR2ARRB2ARRB12727PIK3R2SLC2A4SLC2A4ADIPOQ17PLD1BMP7BMPR1ABMP7BMPR1ASMAD1SMAD5S463S465PRDM16DYNLT1DYNLT3HCRTR1ProgesteroneEpinephrinePRKAA1CAMKK210T172NPY10INS10HCRTR1319GHRLLEPMTORRPS6S2481RPS6KB1S235S236S240S244T389EIF4BRPS6KA1S422S380MTORRRAGCDAGLAGTPCASP915EIF4EBP1T46NFE2L2T3787HMOX17NFE2L27HMOX17CASP3SLC2A13SLC2A12-AGMAPK3MAPK1Y204T202T185STAT3Y187POMCS727POMCGNA11SLC2A113PDHBRUNX1GJA3RARAGLIS1HOMER1LDLRDOK7NPAS4NOCTCLDN4SERP1KCNK3LUZP1NR4A1OPN3PDP1SFPQPER2YARS2TRIM9KLF4CDKN1AHSPA5CCN2MANFNR4A3DUSP4TRA2AOSBPL3TENT5AEGR3EGR1FOSL2EGR2ARCHBEGFMAFFHMGA2JUNBNOGPAPPAGADD45BCXXC5TNCSKILDCLK1ID3FOSLRRC8CIRF5ID1SPP1HES1MYCBHLH40SRFFOSBGLIS2HMGA1ID4KLF10RUNX2ZFP28ZMYM3HAGHLDBPRUNX1T1SGK1SGK1LEPLEP17LEP17, 22VEGFAFLT4NOS3PDP1PRKCAMAPK1MAPK3Glutamicacid uptakeSLC1A2SLC1A2SLC1A2Glutamic acidTFAMCOX7A1UCP1COX8BPDIO2PPARGCEBPACa2+Ca2+Ca2+Ca2+Ca2+Ca2+Ca2+GlucoseHCRTHCRTHCRTHCRTRUNX2SP7ALPPBGLAPCALCAPPOXCOX2GNRH1NPVF12IL612CXCL8MMP3MMP13VCAM15ICAM15SELE5TNFTNFIL1B5, 24IL9IL4IL10NOX4CXCL2PA21AA21PLA2G4A21