Functional selectivity of dopamine receptor agonists. II. Actions of dihydrexidine in D2L receptor-transfected MN9D cells and pituitary lactotrophs.
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".
Kilts
Jason D
JD
Department of Psychiatry, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7160, USA.
Connery
Hilary S
HS
Arrington
Elaine G
EG
Lewis
Mechelle M
MM
Lawler
Cindy P
CP
Oxford
Gerry S
GS
O'Malley
Karen L
KL
Todd
Richard D
RD
Blake
Bonita L
BL
Nichols
David E
DE
Mailman
Richard B
RB
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
D018491:Dopamine Agonists; D010617:Phenanthridines; D015221:Potassium Channels; D017448:Receptors, Dopamine D2; C113776:dopamine D2L receptor; C061532:dihydrexidine; D011388:Prolactin; D004298:Dopamine