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The Journal of Neuroscience, November 1, 1998, 18(21):8692-8699

Selective Activation of G_o by D_2L Dopamine Receptors in NS20Y Neuroblastoma Cells

Val J. Watts¹, Brenda L. Wiens¹, Medhane G. Cumbay¹, Minh N. Vu¹, Rachael L. Neve², and Kim A. Neve¹

¹ Medical Research Service, Veterans Affairs Medical Center, and Department of Behavioral Neuroscience, Oregon Health Sciences University, Portland, Oregon 97201, and ² Department of Genetics, Harvard Medical School, and McLean Hospital, Belmont, Massachusetts 02178

D_2L dopamine receptor activation results in rapid inhibition and delayed heterologous sensitization of adenylate cyclase in several host cell types. The D_2L dopamine receptor was stably transfected into NS20Y neuroblastoma cells to examine inhibition and sensitization in a neuronal cell environment and to identify the particular G-proteins involved. Acute activation of D_2L receptors with the selective D₂ agonist quinpirole inhibited forskolin-stimulated cAMP accumulation, whereas prolonged incubation (2 hr) with quinpirole resulted in heterologous sensitization (more than twofold) of forskolin-stimulated cAMP accumulation in NS20Y-D_2L cells. To unambiguously identify the pertussis toxin (PTX)-sensitive G-proteins responsible for inhibition and sensitization, we used viral-mediated gene delivery to assess the ability of genetically engineered PTX-resistant G-proteins (G_i1*, G_i2*, G_i3*, and G_o*) to rescue both responses after PTX treatment. The expression and function of individual recombinant G-proteins was confirmed with Western blotting and inhibition of GTPS-stimulated adenylate cyclase, respectively. To assess the specificity of D_2L-G coupling, cells were infected with herpes simplex virus (HSV) recombinants expressing individual PTX-resistant G-protein  subunits and treated with PTX, and quinpirole-induced responses were measured. Infection of NS20Y-D_2L cells with HSV-G_o* rescued both inhibition and sensitization in PTX-treated cells, whereas infection with HSV-G_i1*, HSV-G_i2*, or HSV-G_i3* failed to rescue either response. In summary, the current study provides strong evidence that the D_2L dopamine receptor couples to G_o in neuronal cells, and that this coupling is responsible for both the acute and subacute effects of D₂ receptor activation on adenylate cyclase activity.

Key words: dopamine D_2L receptors; G_i/o; NS20Y neuroblastoma; adenylate cyclase; pertussis toxin; heterologous sensitization

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Copyright © 1998 Society for Neuroscience  0270-6474/98/18218692-08$05.00/0

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