Journal
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Volume 301, Issue 3, Pages 1179-1189Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/jpet.301.3.1179
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Funding
- NICHD NIH HHS [HD-01130] Funding Source: Medline
- NIDA NIH HHS [DA-07244] Funding Source: Medline
- NIEHS NIH HHS [ES-07126] Funding Source: Medline
- NIMH NIH HHS [MH-03327, MH-53356, MH-42705, MH-40537, MH-14277] Funding Source: Medline
- NINDS NIH HHS [NS-18788] Funding Source: Medline
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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 [H-3] dopamine in a concentration-responsive, antagonist-reversible manner. Conversely, neither DHX, nor its analogs, inhibited K+-stimulated [H-3] 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.
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