Differential Activation of Adenylate Cyclase and Receptor Internalization by Novel Dopamine D₁ Receptor Agonists

Abstract

Structurally dissimilar dopamine D 1 receptor agonists were compared with dopamine in their ability to activate adenylate cyclase and to internalize hemagglutinin-tagged human D 1 receptors in a stably transfected human embryonic kidney cell line. Thirteen dopamine D 1 receptor agonists were selected rationally from three different structural classes: rigid fused ring compounds [dihydrexidine, dinapsoline, dinoxyline, apomorphine, and (5aR,11bS)-4,5,5a,6,7,11b-hexahydro-2-propyl-3-thia-5-azacyclopent-1-ena[c]-phenanthrene-9,

Aripiprazole has Functionally Selective Actions at Dopamine D2 Receptor-Mediated Signaling Pathways

“…More recent evidence indicates, however, that certain antagonists can internalize certain receptors (Berry et al, 1996;Roettger et al, 1997), and that the internalization process can be agonist-specific depending on the cellular milieu specific to that receptor expression system (Ryman-Rasmussen et al, 2005). These observations complement the fundamentals of functional selectivity, which state that the intrinsic activity of a ligand Functional data represent the means7SEM (in nM) of three to five independent experiments.…”

“…Our study indicates that neither aripiprazole nor the typical partial agonist (À)3PPP induce a significant degree of internalization relative to basal levels, indicating that either D 2 ligands with low intrinsic activity fail to produce D 2 receptor internalization or that these two compounds are unique in their promotion of receptor conformations that cannot be phosphorylated by the appropriate kinases. Although (À)3PPP can desensitize the D 2 receptor (Lahti et al, 1998), it is clear that this does not necessarily predict internalization (Lewis et al, 1998;Ryman-Rasmussen et al, 2005). Further experiments are needed to determine whether D 2 receptor internalization is a product unique to ligands that are full agonists, or if aripiprazole and (À)3PPP are unique in their inability to internalize the D 2 receptor.…”

Evaluating Cellular Impedance Assays for Detection of GPCR Pleiotropic Signaling and Functional Selectivity

“…In studies using D1-HEK cells, synthetic ligands were identified that induced cAMP production, but not receptor internalization, and others that were super agonists for internalization. 22 SK-N-MC cells endogenously express D1, but not D5 receptors, 21,26 and therefore represent a useful cell line to compare the pharmacology between endogenously expressed/coupled D1 receptors to D1-transfected cells. In contrast to the results with D1-HEKs, the native ligand and four synthetic agonists all induced a Gi/o impedance response in SK-N-MC cells.…”

“…This was also true in the adenylate cyclase assay using D1-HEK cells. 22 Both partial agonists had greater efficacy in U-2 cells than in SK-N-MC cells. The greater efficacy for a Gs-like response could reflect biased coupling by these ligands, but could also be due to cellular or assay differences that are not understood.…”

“…Using D1-HEK cells, Ryman-Rasmussen et al 22,23 identified agonists with different pathway bias for stimulating adenylate cyclase and inducing receptor internalization. SKF83959 and SKF38393 were partial agonists at stimulating cAMP production, but did not induce D1 internalization.…”