Interaction of D 3 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 D 2L , D 2S , and D 3 receptors: potent stimulation of mitogen-activated protein kinases and G protein-coupled inward rectifier potassium channels

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.