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Molecular and Cellular Biology, March 2000, p. 1497-1506, Vol. 20, No. 5
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Distinct Roles for Galpha i2 and Gbeta gamma in Signaling to DNA Synthesis and Galpha i3 in Cellular Transformation by Dopamine D2S Receptor Activation in BALB/c 3T3 Cells

Mohammad H. Ghahremani,1 Christine Forget,2 and Paul R. Albert2,*

Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada H3G 1Y6,1 and Neuroscience Research Institute, University of Ottawa, Ottawa, Canada K1H 8M52

Received 12 August 1999/Returned for modification 15 September 1999/Accepted 15 November 1999

Control of cell proliferation depends on intracellular mediators that determine the cellular response to external cues. In neuroendocrine cells, the dopamine D2 receptor short form (D2S receptor) inhibits cell proliferation, whereas in mesenchymal cells the same receptor enhances cell proliferation. Nontransformed BALB/c 3T3 fibroblast cells were stably transfected with the D2S receptor cDNA to study the G proteins that direct D2S signaling to stimulate cell proliferation. Pertussis toxin inactivates Gi and Go proteins and blocks signaling of the D2S receptor in these cells. D2S receptor signaling was reconstituted by individually transfecting pertussis toxin-resistant Galpha i/o subunit mutants and measuring D2-induced responses in pertussis toxin-treated cells. This approach identified Galpha i2 and Galpha i3 as mediators of the D2S receptor-mediated inhibition of forskolin-stimulated adenylyl cyclase activity; Galpha i2-mediated D2S-induced stimulation of p42 and p44 mitogen-activated kinase (MAPK) and DNA synthesis, whereas Galpha i3 was required for formation of transformed foci. Transfection of toxin-resistant Galpha i1 cDNA induced abnormal cell growth independent of D2S receptor activation, while Galpha o inhibited dopamine-induced transformation. The role of Gbeta gamma subunits was assessed by ectopic expression of the carboxyl-terminal domain of G protein receptor kinase to selectively antagonize Gbeta gamma activity. Mobilization of Gbeta gamma subunits was required for D2S-induced calcium mobilization, MAPK activation, and DNA synthesis. These findings reveal a remarkable and distinct G protein specificity for D2S receptor-mediated signaling to initiate DNA synthesis (Galpha i2 and Gbeta gamma ) and oncogenic transformation (Galpha i3), and they indicate that acute activation of MAPK correlates with enhanced DNA synthesis but not with transformation.

* Corresponding author. Mailing address: Neuroscience Research Institute, 451 Smyth Road, Room 2464, Ottawa, Canada K1H 8M5. Phone: (613) 562-5800, ext. 8307. Fax: (613) 562-5403. E-mail: palbert{at}uottawa.ca.

Molecular and Cellular Biology, March 2000, p. 1497-1506, Vol. 20, No. 5
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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