title: Cell contact-dependent functional selectivity of β2-adrenergic receptor ligands in stimulating cAMP accumulation and extracellular signal-regulated kinase phosphorylation.
abstract: Activation of β(2)-adrenegic receptor (β(2)-AR) leads to an increase in intracellular cAMP and activation of ERK. These two signals are activated by the interaction of the receptor with different transducer partners. We showed that the intrinsic activities of β(2)-AR ligands for stimulating cAMP production and ERK phosphorylation responses in HEK-293 cells were not correlated. The lack of correlation resulted mainly from the discrepancy between the intrinsic activities of two groups of ligands for these two responses: The first group consisted of clenbuterol, cimaterol, procaterol, and terbutaline which acted as full agonists for cAMP production but displayed very weak effect on ERK phosphorylation. The second group comprised adrenaline and noradrenaline which displayed higher intrinsic activity for the ERK phosphorylation than for the cAMP response. Thus, both groups behaved as functionally selective ligands. The functional selectivity of the first group was observable only in adherent cells when confluence was approximately 100%. When cell-cell contact was minimized either by decreasing the density of the adherent cells or by bringing the cells into suspension, the first group of ligands gained the ability to stimulate ERK phosphorylation without a change in their effect on cAMP production. In contrast, selectivity of the second group was independent of the adherence state of the cells. Our results show that the inherent "bias" of ligands in coupling a G protein-coupled receptor to different transducers may not always be revealed as functional selectivity when there is a "cross-talk" between the signaling pathways activated by the same receptor.
authors.affiliation: Department of Pharmacology, Ankara University, Faculty of Medicine, 06100 Ankara, Turkey.
authors.forename: Ali I
authors.initials: AI
authors.lastname: Kaya
authors.forename: H Ongun
authors.initials: HO
authors.lastname: Onaran
authors.forename: Gülnihal
authors.initials: G
authors.lastname: Özcan
authors.forename: Caterina
authors.initials: C
authors.lastname: Ambrosio
authors.forename: Tommaso
authors.initials: T
authors.lastname: Costa
authors.forename: Sezen
authors.initials: S
authors.lastname: Balli
authors.forename: Özlem
authors.initials: Ö
authors.lastname: Ugur
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D019390:Arrestins / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000502:physiology*; D010766:Phosphorylation / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D020239:Receptor Cross-Talk / Q000502:physiology; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D007546:Isoquinolines; D008024:Ligands; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D018343:Receptors, Adrenergic, beta-2; D013449:Sulfonamides; D000071557:beta-Arrestins; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide