Human D2 and D4 dopamine receptors couple through betagamma G-protein subunits to inwardly rectifying K+ channels (GIRK1) in a Xenopus oocyte expression system: selective antagonism by L-741,626 and L-745,870 respectively.
To examine the effects of a novel selective D4 receptor ligand, L-745,870 (3-[4-(4-chlorophenyl)piperazin-1-yl]methyl-1H-pyrrolo[2,3-b]pyrid ine), on human dopamine receptor function, the ability of this ligand to antagonise G-protein gated inwardly rectifying K+ (GIRK/Kir3) currents activated by cloned human D2 and D4 receptors expressed in Xenopus oocytes was examined using voltage-clamp recording. Its effects were also contrasted with that of a selective D2 receptor antagonist L-741,626. L-745,870 had no detectable agonist activity on human D4 receptors and selectively blocked currents activated by D4 but not D2 receptors. The role of G-protein subunits in dopamine receptor modulation of GIRK currents was also examined by co-expression of beta1 and/or gamma2 subunits on spontaneously active and receptor-activated currents. Currents activated by both D2 and D4 receptors were occluded by direct activation of GIRK currents following co-transfection with the cDNA encoding G-protein betagamma subunits. These data demonstrate that L-745,870 and L-741,626 act as antagonists on human D4 and D2 receptors respectively, and that activation of GIRK channels by these dopamine receptors can be disrupted by direct stimulation of K+ currents by G-protein betagamma subunits.
Pillai
G
G
Merck Sharp and Dohme, Neuroscience Research Centre, Harlow, UK.
Brown
N A
NA
McAllister
G
G
Milligan
G
G
Seabrook
G R
GR
D018492:Dopamine Antagonists / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D019204:GTP-Binding Proteins / Q000502:physiology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D015640:Ion Channel Gating; D008564:Membrane Potentials / Q000187:drug effects; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology; D026902:Potassium Channel Blockers; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D050638:Receptors, Dopamine D4
C099630:3-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-1H-pyrrolo(2,3-b)pyridine; C493599:DRD4 protein, human; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D007211:Indoles; D010880:Piperidines; D026902:Potassium Channel Blockers; D011725:Pyridines; D011758:Pyrroles; D050638:Receptors, Dopamine D4; C104750:3-(4-(4-chlorophenyl-4-hydroxypiperidino)methyl)indole; D019204:GTP-Binding Proteins