Interaction of D3 preferring agonist (−)-N 6-(2-(4-(biphenyl-4-yl)piperazin-1-yl)ethyl)-N 6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (D-264) with cloned human D2L, D2S, and D3 receptors: potent stimulation of mitogen-activated protein kinases and G protein-coupled inward rectifier potassium channels

Abstract

This study aims to determine the effect of the novel D(3) dopamine receptor agonist, D-264, on activation of D(3) and D(2) dopamine receptor signal transduction pathways and cell proliferation. AtT-20 neuroendocrine cells stably expressing human D(2S), D(2L), and D(3) dopamine receptors were treated with D-264 and the coupling of the receptors to mitogen-activated protein kinase (MAPK) and G protein-coupled inward rectifier potassium (GIRK) channels was determined using Western blotting and whole-cell voltage clamp recording, respectively. D-264 potently activated MAPK signaling pathway coupled to D(2S), D(2L), and D(3) dopamine receptors. The activation of MAPK was more pronounced than the reference agonist quinpirole and was longer lasting. D-264 also activated GIRK channels coupled to D(2S), D(2L), and D(3) receptors. In addition, D-264 dose-dependently induced cell proliferation in AtT-D(2L) and AtT-D(3) cells. These results indicate that D-264 robustly activates GIRK channels and MAPK coupled to D(2) and D(3) dopamine receptors in AtT-20 cells. D-264 is also a potent inducer of cell proliferation.