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Regions in the G Protein Subunit Important for Interaction with Receptors and Effectors

Laboratory in Pharmacology, College of Pharmacy, Chungnam National University Daejeon, Korea (C.-S.M.); Faculty of Medicine and Health Sciences, Universiti Malaysia Sarawak, Kuching, Sarawak, Malaysia (W.K.L.); Department of Gastroenterology, Showa University, Yokohama, Japan (H.Y.); Departments of Pharmacology and Medicine, University of Michigan, Ann Arbor, Michigan (R.R.N.); and Department of Pharmacology, University of Virginia Health Sciences Center, Charlottesville, Virginia (J.M.D., J.C.G.)

G dimers containing the ₁₁ or ₁ subunits are often less potent and effective in their ability to regulate effectors compared with dimers containing the subunit. To explore the regions of the ₂ subunit that affect the activity of the dimer, we constructed eight chimeric subunits from the ₁ and ₂ subunits. Two chimeras were made in which the N-terminal regions of ₁ and ₂ were exchanged and two in which the C-terminal regions were transposed. Another set of chimeras was made in which the CAAX motifs of the chimeras were altered to direct modification with different prenyl groups. All eight chimeras were expressed in Sf9 cells with the ₁ subunit, G dimers were purified, and then they were assayed in vitro for their ability to bind to the G_i1 subunit, to couple G_i1 to the A1 adenosine receptor, to stimulate phospholipase C-, and to regulate type I or type II adenyl cyclases. Dimers containing the C-terminal sequence of the ₂ subunit modified with the geranylgeranyl lipid had the highest affinity for G_i1 (range, 0.5-1.2 nM) and were most effective at coupling the G_i1 subunit to receptor. These dimers were most effective at stimulating the phosphatidylinositol-specific phospholipase C- isoform and inhibiting type I adenyl cyclase. In contrast, dimers containing the N-terminal sequence of the ₂ subunit and a geranylgeranyl group are most effective at activating type II adenyl cyclase. The results indicate that both the N- and C-terminal regions of the subunit impart specificity to receptor and effector interactions.

Address correspondence to: Dr. James C. Garrison, Department of Pharmacology, University of Virginia Health Sciences Center, P.O. Box 800735, 1300 Jefferson Park Avenue, Charlottesville, VA 22908-0735. E-mail: jcg8w{at}virginia.edu

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