Functional Selectivity of Dopamine Receptor Agonists. II. Actions of Dihydrexidine in D_2LReceptor-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-npropyl-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 concentrationdependent manner in both systems, effects blocked by D 2 , but not D 1 , antagonists. In the MN9D cells, quinpirole and R-(Ϫ)-N-propylnorapomorphine (NPA) also inhibited the K ϩ -stimulated release of [ 3 H]dopamine in a concentration-responsive, antagonist-reversible manner. Conversely, neither DHX, nor its analogs, inhibited K ϩ -stimulated [ 3 H]dopamine release, although they antagonized the effects of quinpirole. S-(ϩ)-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 receptormediated inhibition of adenylate cyclase). In lactotrophs, DHX had little intrinsic activity at D 2 receptors coupled to G proteincoupled 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".The dopamine receptors, members of the G protein-coupled receptor superfamily, are generally divided into two classes, "D 1 -like" and "D 2 -like" (Jaber et al., 1996;Huff, 1997) In the central nervous system, dopamine receptors exist on both dopamine neurons (on soma, dendrites, and terminals) and postsynaptically on target cells. Presynaptic receptors (autoreceptors) fall under the D 2 -like class of dopamine re-

Recruitment of β-arrestin2 to the dopamine D2 receptor: Insights into anti-psychotic and anti-parkinsonian drug receptor signaling

“…MAP kinase and GIRK channel activation) (Gay et al, 2004). However, in an other study SNPA was determined to be a partial agonist with regard to cAMP signaling (Kilts et al, 2002). This discrepancy could arise from spare receptor effects in the heterologous expression system where SNPA was observed to be a full agonist.…”

The Effective Application of Biased Signaling to New Drug Discovery

“…The first molecular description of this phenomenon ascribed this effect to the stabilization of different receptor active states by different agonists (Kenakin and Morgan, 1989;Kenakin, 1995). The ability of agonists to choose signaling pathways has been given a number of names ("stimulus trafficking," Kenakin, 1995; "functional selectivity," Lawler et al, 1999;Kilts et al, 2002;Shapiro et al, 2003;"functional dissociation," Whistler and von Zastrow, 1999; "biased inhibition," Kudlacek et al, 2002;"differential engagement," Manning, 2002); the term "biased signaling" was introduced by Jarpe et al (1998) and is favored as a general descriptor of the effect. It is worth considering the present place of this idea in new drug discovery.…”

Functional Selectivity of D2Receptor Ligands in a Chinese Hamster Ovary hD2LCell Line: Evidence for Induction of Ligand-Specific Receptor States

“…As GPCRs, D 2 receptors mediate these downstream effectors via activation of G␣ i/o and various G␤␥ subunits, as well as other proteins such as G protein-coupled receptor kinases. Studies over the last decade have shown that some D 2 ligands can cause functionally selective signaling both in vivo and in vitro (Lawler et al, 1999;Kilts et al, 2002;Mottola et al, 2002;Shapiro et al, 2003). In the striatum, the dopamine receptor agonist dihydrexidine (DHX) was able to inhibit adenylate cyclase activity with the same maximal intrinsic activity as quinpirole, a prototypical D 2 receptor agonist.…”