OMIMOnlineMendelianInheritanceinManAll DatabasesPubMedNucleotideProteinGenomeStructurePMCTaxonomyOMIM SearchPubMedProteinNucleotideCoreNucleotideGSSESTStructureGenomeBooksCancerChromosomesConservedDomainsdbGaP3DDomainsGeneGenomeProjectGENSATGEOProfilesGEODataSetsHomoloGeneJournalsMeSHNCBIWebSiteNLMCatalogOMIAOMIMPMCPopSetProbeProteinClustersPubChemBioAssayPubChemCompoundPubChemSubstanceSNPTaxonomyToolKitUniGeneUniSTSLimitsPreview/IndexHistoryClipboardDetailsDisplayTitlesDetailedClinicalSynopsisAllelicVariantsASN1XMLLinkOutRelatedEntriesBookLinksGeneLinksGenomeLinksGEOProfileLinksHomoloGeneLinksNucleotideLinksOMIALinksPubChemBioAssayLinksPMCLinksProteinLinksPubMed(calculated)LinksPubMed(cited)LinksSNPLinksGeneGenotypeLinksStructureLinksUniGeneLinksUniSTSLinksShow5102050100200500SendtoTextFilePrinterClipboardAll1OMIMdbSNP0OMIMUniSTS0*102980LinksADENYLATECYCLASEACTIVATINGPOLYPEPTIDE1ADCYAP1AlternativetitlessymbolsPITUITARYADENYLATECYCLASEACTIVATINGPOLYPEPTIDEPACAPPACAP38INCLUDEDPACAP27INCLUDEDPACAPRELATEDPEPTIDEINCLUDEDPRPINCLUDEDGenemaplocus18p11TEXTCLONINGPituitaryadenylatecyclaseactivatingpolypeptide(PACAP)isabioactivepeptidethatwasoriginallyisolatedfromovinehypothalamusonthebasisofitsabilitytostimulateadenylatecyclaseinratanteriorpituitarycellculturesTheNterminalaminoacidsequenceofPACAPshares68%identitywithvasoactiveintestinalpeptide(VIP192320)andmorelimitedsimilaritywithgrowthhormonereleasinghormone(GHRH139190)Hosoyaetal(1992)clonedhumanPACAPThededuced176aminoacidprecursorproteincontainsanNterminalsignalpeptideacentralPACAPrelatedpeptide(PRP)sequenceandtheCterminalbioactivepeptidesequenceThereare2maturePACAPpeptidesPACAP38andPACAP27ashorterformcorrespondingtotheNterminal27aminoacidsofPACAP38GENEFUNCTIONFresonetal(2004)described2relatedpatientswithapartialtrisomy18p3copiesofthePACAPgeneandelevatedPACAPplasmaconcentrationsInadditiontoseverementalretardationthepatientshadableedingtendencywithmildthrombocytopeniaandtheirfibroblastsshowedincreasedPACAPmRNAlevelsTheyalsohadincreasedbasalcAMPlevelsinplateletsandfibroblastsprovidingabasisfortheobservedreductioninplateletaggregationFresonetal(2004)foundthatmegakaryocytespecifictransgenicoverexpressionofPACAPinmicecorrespondinglyincreasedPACAPreleasefromplateletsreducedplateletactivationandprolongedthetailbleedingtimeInhibitionofPACAPbyanantagonistorantibodyenhancedthecollageninducedaggregationofnormalhumanplateletsandanincreasedplateletsensitivitytowardcollagenwasfoundinPACAPknockoutmiceFresonetal(2004)concludedthatPACAPmodulatesplateletfunctionandthattheirpatientsrepresentedthefirstreportedhemostaticdefectassociatedwithPACAPoverexpressionMerceretal(2004)foundthatculturedneuralstemcellsisolatedfromthelateralventriclewallofadultmiceexpressedPac1(102981)andproliferatedinvitroinresponsetothePac1agonistsPacapandmaxadilanbutnotVip(192320)atphysiologicconcentrationsindicatingthatPac1isamediatorofneuralstemcellproliferationPharmacologicandbiochemicalcharacterizationofPacapinducedneuralstemcellproliferationrevealedthatproteinkinaseC(seePRKCA176960)signalingwastheprincipalpathwayactivatedandadditionofEgf(131530)synergisticallyenhancedtheproliferatingeffectofPacapPacapstimulatedculturedneuralstemcellstoformmultipotentneurosphereswiththecapacitytogeneratebothneuronalandglialcellsIntracerebroventricularinfusionofPacapincreasedcellproliferationintheventricularzoneofthelateralventricleandthedentategyrusofthehippocampusMerceretal(2004)concludedthatPACAPthroughPAC1isapotentmediatorofadultneuralstemcellproliferationGENESTRUCTUREHosoyaetal(1992)determinedthattheADCYAP1genecontains5exonsandspansabout7kbTheputativepromoterregioncontainsCREandTREelementsandaGHF1(173110)bindingsitebutnoapparentTATACCAATorGCboxesMAPPINGOnthebasisofDNAisolatedfromamouseA9microcellhybridclonecontainingasinglehumanchromosomeHosoyaetal(1992)assignedthePACAPgenetochromosome18itwasregionalizedto18p11byinsituhybridizationMOLECULARGENETICSPerezJuradoandFrancke(1993)describedadinucleotiderepeatpolymorphisminthe3primeuntranslatedregionofthePACAPgeneEVOLUTIONHumanevolutionischaracterizedbyadramaticincreaseinbrainsizeandcomplexityToprobeitsgeneticbasisDorusetal(2004)examinedtheevolutionofgenesinvolvedindiverseaspectsofnervoussystembiologyThesegenesincludingADCYAP1displayedsignificantlyhigherratesofproteinevolutioninprimatesthaninrodentsThistrendwasmostpronouncedforthesubsetofgenesimplicatedinnervoussystemdevelopmentMoreoverwithinprimatestheaccelerationofproteinevolutionwasmostprominentinthelineageleadingfromancestralprimatestohumansDorusetal(2004)concludedthatthephenotypicevolutionofthehumannervoussystemhasasalientmolecularcorrelateieacceleratedevolutionoftheunderlyinggenesparticularlythoselinkedtonervoussystemdevelopmentANIMALMODELPACAPhasbeenconservedremarkablyduringevolutionandiswidelyexpressedinthemammalianbrainInDrosophilamutationofthePACAPhomologresultsinbehavioraldefectsincludingimpairedolfactoryassociatedlearningandchangesinethanolsensitivityHashimotoetal(2001)reportedthegenerationofmicelackingthePACAPgeneThesemicewerebornintheexpectedmammalianratiosbuthadahighearlymortalityrateThesurvivingadultPACAP/micedisplayedremarkablebehavioralchangeshyperactiveandexplosivejumpingbehaviorsinanopenfieldincreasedexploratorybehaviorandlessanxietyintheelevatedplusmazeemergenceandnovelobjecttestsAnalysisofthebrainsofPACAP/micerevealedthattheserotoninmetabolite5hydroxyindoleaceticacidwasslightlydecreasedinthecortexandstriatumcomparedwithwildtypemiceThusPACAPplaysapreviouslyuncharacterizedroleintheregulationofpsychomotorbehaviorsTheadrenalglandisimportantforhomeostaticresponsestometabolicstresshypoglycemiastimulatesthesplanchnicnerveepinephrineisreleasedfromadrenomedullarychromaffincellsandcompensatoryglucogenesisensuesAcetylcholineistheprimaryneurotransmittermediatingcatecholaminesecretionfromtheadrenalmedullaHamelinketal(2002)addedtotheaccumulatingevidencethatasecretinrelatedneuropeptidealsomayfunctionasatransmitterattheadrenomedullarysynapseCostainingwithhighlyspecificantibodiesagainstPACAPrevealedthatitisfoundinnerveendingsatallmouseadrenomedullarycholinergicsynapsesMicewithatargeteddeletionofthePACAPgenehadotherwisenormalcholinergicinnervationandmorphologyoftheadrenalmedullanormaladrenalcatecholamineandbloodglucoselevelsandanintactinitialcatecholaminesecretoryresponsetoinsulininducedhypoglycemiaHoweverinsulininducedhypoglycemiawasmoreprofoundandlongerlastinginPACAPknockoutsandwasassociatedwithadoserelatedlethalityabsentinwildtypemiceFailureofPacapdeficientmicetocounterregulateadequatelyplasmaglucoselevelscouldbeaccountedforbyimpairedlongtermsecretionofepinephrinesecondarytoalackofinductionoftyrosinehydroxylasenormallyoccurringafterinsulinhypoglycemiainwildtypemiceandaconsequentdepletionofadrenomedullaryepinephrinestoresThusHamelinketal(2002)concludedthatPACAPisneededtocoupleepinephrinebiosynthesistosecretionduringmetabolicstressPACAPappearstofunctionasan'emergencyresponse'cotransmitterinthesympathoadrenalaxiswheretheprimarysecretoryresponseiscontrolledbyaclassicneurotransmitterbutsustainedunderparaphysiologicconditionsbyaneuropeptideREFERENCES1DorusSVallenderEJEvansPDAndersonJRGilbertSLMahowaldMWyckoffGJMalcomCMLahnBTAcceleratedevolutionofnervoussystemgenesintheoriginofHomosapiensCell119102710402004PubMedID156203602FresonKHashimotoHThysCWittevrongelCDanloySMoritaYShintaniNTomiyamaYVermylenJHoylaertsMFBabaAVanGeetCThepituitaryadenylatecyclaseactivatingpolypeptideisaphysiologicalinhibitorofplateletactivationJClinInvest1139059122004PubMedID150673233HamelinkCTjurminaODamadzicRYoungWSWeiheELeeHWEidenLEPituitaryadenylatecyclaseactivatingpolypeptideisasympathoadrenalneurotransmitterinvolvedincatecholamineregulationandglucohomeostasisProcNatAcadSci994614662002PubMedID117566844HashimotoHShintaniNTanakaKMoriWHiroseMMatsudaTSakaueMMiyazakiJNiwaHTashiroFYamamotoKKogaKTomimotoSKunugiASuetakeSBabaAAlteredpsychomotorbehaviorsinmicelackingpituitaryadenylatecyclaseactivatingpolypeptide(PACAP)ProcNatAcadSci9813355133602001PubMedID116876155HosoyaMKimuraCOgiKOhkuboSMiyamotoYKugohHShimizuMOndaHOshimuraMArimuraAFujinoMStructureofthehumanpituitaryadenylatecyclaseactivatingpolypeptide(PACAP)geneBiochimBiophysActa11291992061992PubMedID17300606MercerARonnholmHHolmbergJLundhHHeidrichJZachrissonOOssoinakAFrisenJPatroneCPACAPpromotesneuralstemcellproliferationinadultmousebrainJNeurosciRes762052152004PubMedID150489187PerezJuradoLAFranckeUDinucleotiderepeatpolymorphismatthehumanpituitaryadenylatecyclaseactivatingpolypeptide(PACAP)geneHumMolecGenet2827only1993PubMedID8353512CONTRIBUTORSPatriciaAHartzupdated6/23/2005StylianosEAntonarakisupdated1/10/2005PatriciaAHartzupdated6/18/2004MarlaJFO'Neillupdated5/20/2004VictorAMcKusickupdated6/3/2002VictorAMcKusickupdated12/14/2001CREATIONDATEVictorAMcKusick7/8/1993EDITHISTORYwwang8/3/2005wwang7/21/2005terry6/23/2005mgross1/10/2005mgross6/24/2004terry6/18/2004mgross6/10/2004terry6/8/2004carol6/8/2004terry5/20/2004cwells6/26/2002terry6/3/2002alopez12/18/2001terry12/14/2001alopez8/25/1998alopez9/3/1997carol8/31/1993carol7/8/1993Copyright©19662007JohnsHopkinsUniversityDisplayTitlesDetailedClinicalSynopsisAllelicVariantsASN1XMLLinkOutRelatedEntriesBookLinksGeneLinksGenomeLinksGEOProfileLinksHomoloGeneLinksNucleotideLinksOMIALinksPubChemBioAssayLinksPMCLinksProteinLinksPubMed(calculated)LinksPubMed(cited)LinksSNPLinksGeneGenotypeLinksStructureLinksUniGeneLinksUniSTSLinksShow5102050100200500SendtoTextFilePrinterClipboardDisclaimerWritetotheHelpDeskPrivacyPolicyNCBINLMNIH