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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

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Abstract

This study aims to determine the effect of the novel D3 dopamine receptor agonist, D-264, on activation of D3 and D2 dopamine receptor signal transduction pathways and cell proliferation. AtT-20 neuroendocrine cells stably expressing human D2S, D2L, and D3 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 D2S, D2L, and D3 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 D2S, D2L, and D3 receptors. In addition, D-264 dose-dependently induced cell proliferation in AtT-D2L and AtT-D3 cells. These results indicate that D-264 robustly activates GIRK channels and MAPK coupled to D2 and D3 dopamine receptors in AtT-20 cells. D-264 is also a potent inducer of cell proliferation.

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Acknowledgments

This work is supported by the National Institute of Neurological Disorders and Stroke/National Institute of Health (NS047198, AKD) and the F.M. Kirby Foundation (EVK).

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Authors and Affiliations

  1. Department of Pharmacology & Physiology, UMDNJ-New Jersey Medical School, Newark, NJ, 07103, USA

    Eldo V. Kuzhikandathil & Samantha Cote

  2. Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI, 48202, USA

    Soumava Santra & Aloke K. Dutta

  3. Department of Pharmaceutical Sciences, Applebaum College of Pharmacy & Health Sciences, Rm# 3128, Detroit, MI, 48202, USA

    Aloke K. Dutta

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  1. Eldo V. Kuzhikandathil
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  2. Samantha Cote
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  3. Soumava Santra
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  4. Aloke K. Dutta
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Correspondence to Aloke K. Dutta.

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Kuzhikandathil, E.V., Cote, S., Santra, S. et al. 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. Naunyn-Schmiedeberg's Arch Pharmacol 386, 97–105 (2013). https://doi.org/10.1007/s00210-012-0811-6

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