title: Functional selectivity of dopamine receptor agonists. II. Actions of dihydrexidine in D2L receptor-transfected MN9D cells and pituitary lactotrophs.
abstract: D(2)-like dopamine receptors mediate functional changes via activation of inhibitory G proteins, including those that affect adenylate cyclase activity, and potassium and calcium channels. Although it is assumed that the binding of a drug to a single isoform of a D(2)-like receptor will cause similar changes in all receptor-mediated functions, it has been demonstrated in brain that the dopamine agonists dihydrexidine (DHX) and N-n-propyl-DHX are "functionally selective". The current study explores the underlying mechanism using transfected MN9D cells and D(2)-producing anterior pituitary lactotrophs. Both dopamine and DHX inhibited adenylate cyclase activity in a concentration-dependent manner in both systems, effects blocked by D(2), but not D(1), antagonists. In the MN9D cells, quinpirole and R-(-)-N-propylnorapomorphine (NPA) also inhibited the K(+)-stimulated release of [(3)H]dopamine in a concentration-responsive, antagonist-reversible manner. Conversely, neither DHX, nor its analogs, inhibited K(+)-stimulated [(3)H]dopamine release, although they antagonized the effects of quinpirole. S-(+)-NPA actually had the reverse functional selectivity profile from DHX (i.e., it was a full agonist at D(2L) receptors coupled to inhibition of dopamine release, but a weak partial agonist at D(2L) receptor-mediated inhibition of adenylate cyclase). In lactotrophs, DHX had little intrinsic activity at D(2) receptors coupled to G protein-coupled inwardly rectifying potassium channels, and actually antagonized the effects of dopamine at these D(2) receptors. Together, these findings provide compelling evidence for agonist-induced functional selectivity with the D(2L) receptor. Although the underlying molecular mechanism is controversial (e.g., "conformational induction" versus "drug-active state selection"), such data are irreconcilable with the widely held view that drugs have "intrinsic efficacy".
authors.affiliation: Department of Psychiatry, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7160, USA.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Kilts
authors.forename: Hilary S
authors.initials: HS
authors.lastname: Connery
authors.forename: Elaine G
authors.initials: EG
authors.lastname: Arrington
authors.forename: Mechelle M
authors.initials: MM
authors.lastname: Lewis
authors.forename: Cindy P
authors.initials: CP
authors.lastname: Lawler
authors.forename: Gerry S
authors.initials: GS
authors.lastname: Oxford
authors.forename: Karen L
authors.initials: KL
authors.lastname: O'Malley
authors.forename: Richard D
authors.initials: RD
authors.lastname: Todd
authors.forename: Bonita L
authors.initials: BL
authors.lastname: Blake
authors.forename: David E
authors.initials: DE
authors.lastname: Nichols
authors.forename: Richard B
authors.initials: RB
authors.lastname: Mailman
mesh_terms: D000818:Animals; D002460:Cell Line; D004298:Dopamine / Q000502:physiology; D018491:Dopamine Agonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D010617:Phenanthridines / Q000494:pharmacology*; D010903:Pituitary Gland, Anterior / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism; D011388:Prolactin / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000502:physiology; D014162:Transfection / Q000379:methods / Q000706:statistics & numerical data
chemical_list: D018491:Dopamine Agonists; D010617:Phenanthridines; D015221:Potassium Channels; D017448:Receptors, Dopamine D2; C113776:dopamine D2L receptor; C061532:dihydrexidine; D011388:Prolactin; D004298:Dopamine