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Functional Selectivity of D₂ Receptor Ligands in a Chinese Hamster Ovary hD_2L Cell Line: Evidence for Induction of Ligand-Specific Receptor States

Departments of Psychiatry (R.B.M.), Pharmacology (R.B.M.), Cellular and Molecular Physiology (G.S.O.), Neuroscience Center (G.S.O., R.B.M.), the Curriculum in Neurobiology (E.A.G.), and the Curriculum in Toxicology (J.D.U.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and Departments of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana (D.E.N.)

There are now several examples of single G protein-coupled receptors to which binding of specific agonists causes differential effects on the associated signaling pathways. The dopamine D₂ receptor is of special importance because the selective activation of functional pathways has been shown both in vitro and in situ. For this reason, the present work characterized a series of rigid D₂ agonists in Chinese hamster ovary cells transfected with the human D_2L receptor using three distinct functional endpoints: inhibition of cAMP synthesis, stimulation of mitogen-activated protein (MAP) kinase phosphorylation, and activation of G protein-coupled inwardly rectifying potassium channels (GIRKs). In this system, S-propylnorapomorphine (SNPA), R-propylnorapomorphine (RNPA), dihydrexidine (DHX), dinapsoline (DNS), and dinoxyline (DNX) all inhibited forskolin-stimulated adenylate cyclase activity to the same extent as the prototypical D₂ agonist quinpirole (QP). The rank order of potency was the following: RNPA >> QP = DNX > SNPA > DHX = DNS. For MAP kinase phosphorylation, DHX, DNS, DNX, and RNPA had efficacy similar to QP, whereas SNPA was a partial agonist. The rank order of potency for MAP kinase phosphorylation was RNPA >> QP = DNX > DHX > DNS = SNPA. DNX activated GIRK channels to the same extent as QP, whereas DHX and DNS were partial agonists, and RNPA and SNPA caused no appreciable activation. These findings indicate that DHX, DNS, RNPA, and SNPA have atypical functional properties at the hD_2L receptor and display different patterns of functional selectivity. We hypothesize that this functional selectivity may be a result of ligand induction of specific conformations of the D_2L receptor that activate only selected signaling pathways.

Address correspondence to: Dr. Richard B. Mailman, CB #7160, Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7160. E-mail: Richard_Mailman{at}med.unc.edu

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