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J Biol Chem, Vol. 274, Issue 14, 9238-9245, April 2, 1999

Distinct Roles for G_i2, G_i3, and G in Modulation of Forskolin- or G_s-mediated cAMP Accumulation and Calcium Mobilization by Dopamine D2S Receptors

Mohammad H. Ghahremani, Peihua Cheng^¶, Paola M. C. Lembo, and Paul R. Albert^¶

From the  Department of Pharmacology and Therapeutics, McGill University, Montreal H3G 1Y6, Canada and the ^¶ Neuroscience Research Institute, University of Ottawa, Ottawa K1H 8M5, Canada

Previous studies have shown that a single G protein-coupled receptor can regulate different effector systems by signaling through multiple subtypes of heterotrimeric G proteins. In LD2S fibroblast cells, the dopamine D2S receptor couples to pertussis toxin (PTX)-sensitive G_i/G_o proteins to inhibit forskolin- or prostaglandin E₁-stimulated cAMP production and to stimulate calcium mobilization. To analyze the role of distinct G_i/o protein subtypes, LD2S cells were stably transfected with a series of PTX-insensitive G_i/o protein Cys  Ser point mutants and assayed for D2S receptor signaling after PTX treatment. The level of expression of the transfected G mutant subunits was similar to the endogenous level of the most abundant G_i/o proteins (G_o, G_i3). D2S receptor-mediated inhibition of forskolin-stimulated cAMP production was retained only in clones expressing mutant G_i2. In contrast, the D2S receptor utilized G_i3 to inhibit PGE₁-induced (G_s-coupled) enhancement of cAMP production. Following stable or transient transfection, no single or pair set of mutant G_i/o subtypes rescued the D2S-mediated calcium response following PTX pretreatment. On the other hand, in LD2S cells stably transfected with GRK-CT, a receptor kinase fragment that specifically antagonizes G subunit activity, D2S receptor-mediated calcium mobilization was blocked. The observed specificity of G_i2 and G_i3 for different states of adenylyl cyclase activation suggests a higher level of specificity for interaction of G_i subunits with forskolin- versus G_s-activated states of adenylyl cyclase than has been previously appreciated.

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