INVESTIGADORES
DAVIO Carlos Alberto
artículos
Título:
Physiological implications of biased signaling at histamine H2 receptors.
Autor/es:
ALONSO NATALIA; ZAPPIA DANIEL; CABRERA MAIA; DAVIO CARLOS; SHAYO CARINA; MONCZOR FEDERICO; FERNADEZ NATALIA
Revista:
Front Pharmacol
Editorial:
Frontiers
Referencias:
Año: 2015 vol. 6 p. 1 - 9
ISSN:
1663-9812
Resumen:
HistaminemediatesnumerousfunctionsactingthroughitsfourreceptorsubtypesallbelongingtothelargefamilyofseventransmembraneG-proteincoupledreceptors.Inparticular,histamineH2receptor(H2R)ismainlyinvolvedingastricacidproduction,becomingaclassicpharmacologicaltargettotreatZollinger?Ellisondiseaseandgastricandduodenalulcers.H2ligandsrankamongthemostwidelyprescribedandoverthecounter-solddrugsintheworld.RecentevidenceindicatethatsomeH2Rligandsdisplaybiasedagonism,selectingandtriggeringsome,butnotall,ofthesignalingpathwaysassociatedtotheH2R.Theaimofthepresentworkistostudywhetherfamotidine,clinicallywidespreadusedligandactingatH2R,exertsbiasedsignaling.OurfindingsindicatethatwhilefamotidineactsasinverseagonistdiminishingcAMPbasallevels,itmimicstheeffectsofhistamineandtheagonistamthamineconcerningreceptordesensitizationandinternalization.Moreover,thetreatmentofHEK293TtransfectedcellswithanyofthethreeligandsleadtoaconcentrationdependentpERKincrement.SimilarlyinAGSgastricepithelialcells,famotidinetreatmentledtoboth,thereductionincAMPlevelsaswellastheincrementinERKphosphorylation,suggestingthatthisbehaviorcouldhavepharmacologicalrelevantimplications.Basedonthat,histidinedecarboxylaseexpressionwasstudiedbyquantitativePCRinAGScellsanditslevelswereincreasedbyfamotidineaswellasbyhistamineandamthamine.Inallcases,thepositiveregulationwasimpededbytheMEKinhibitorPD98059,indicatingthatbiasedsignalingtowardERK1/2pathwayistheresponsibleofsuchenzymeregulation.Theseresultssupportthatligandbiasisnotonlyapharmacologicalcuriositybuthasphysiologicalandpharmacologicalimplicationsoncellmetabolism.
