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J. Biol. Chem., Vol. 279, Issue 3, 1601-1606, January 16, 2004

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A Region of the Third Intracellular Loop of the Short Form of the D2 Dopamine Receptor Dictates G_i Coupling Specificity^*

Susan E. Senogles, Tamra L. Heimert, Emilia Riviera Odife, and Michael W. Quasney¶

From the Department of Molecular Sciences, University of Tennessee Health Science Center, College of Medicine, and the ^¶Department of Pediatrics, LeBonheur Children's Medical Center, Memphis, Tennessee 38163

The D2 dopamine receptor has two isoforms, the short form (D2s receptor) and the long form (D2l receptor), which differ by the presence of a 29-amino acid insert in the third cytoplasmic loop. Both the D2s and D2l receptors have been shown to couple to members of the G_i family of G proteins, but whether each isoform couples to specific G_i protein(s) remains controversial. In previous studies using G_i mutants resistant to modification by pertussis toxin (G_iPT), we demonstrated that the D2s receptor couples selectively to G_i2PT and that the D2l receptor couples selectively to G_i3PT (Senogles, S. E. (1994) J. Biol. Chem. 269, 23120–23127). In this study, two point mutations of the D2s receptor were created by random mutagenesis (R233G and A234T). The two mutant D2s receptors demonstrated pharmacological characteristics comparable with those of the wild-type D2s receptor, with similar agonist and antagonist binding affinities. We used human embryonic kidney 293 cells stably transfected with G_i1PT, G_i2PT, or G_i3PT to measure agonist-mediated inhibition of forskolin-stimulated cAMP accumulation before and after pertussis toxin treatment. The two mutant D2s receptors demonstrated a change in G_i coupling specificity compared with the wild-type D2s receptor. Whereas the wild-type D2s receptor coupled predominantly to G_i2PT, mutant R233G coupled preferentially to G_i3PT, and mutant A234T coupled preferentially to G_i1PT. These results suggest that this region of the third cytoplasmic loop is crucial for determining G_i protein coupling specificity.

Received for publication, September 3, 2003 , and in revised form, October 21, 2003.

^* This work was supported by United States Public Health Service Grant NS28811 (to S. E. S.) and by a grant from the University of Tennessee Health Science Center. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Molecular Sciences, University of Tennessee Health Science Center, 858 Madison Ave., Suite G01, Memphis, TN 38163. Tel.: 901-448-7077; Fax: 901-448-7360; E-mail: ssenogles{at}utmem.edu.

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