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Volume 272, Number 1, Issue of January 3, 1997 pp. 337-344
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

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Identification of A_2a Adenosine Receptor Domains Involved in Selective Coupling to G_S
ANALYSIS OF CHIMERIC A₁/A_2a ADENOSINE RECEPTORS

(Received for publication, October 25, 1996)

From the Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710

Responses to adenosine are governed by selective activation of distinct G proteins by adenosine receptor (AR) subtypes. The A_2aAR couples via G_s to adenylyl cyclase stimulation while the A₁AR couples to G_i to inhibit adenylyl cyclase. To determine regions of the A_2aAR that selectively couple to G_s, chimeric A₁/A_2aARs were expressed in Chinese hamster ovary cells and ligand binding and adenylyl cyclase activity analyzed. Replacement of the third intracellular loop of the A_2aAR with that of the A₁AR reduced maximal adenylyl cyclase stimulation and decreased agonist potency. Restricted chimeras indicated that the NH₂-terminal portion of intracellular loop 3 was predominantly responsible for this impairment. Reciprocal chimeras composed primarily of A₁AR sequence with limited A_2aAR sequence substitution stimulated adenylyl cyclase and thus supported these findings. A lysine and glutamic acid residue were identified as necessary for efficient A_2aAR-G_s coupling. Analysis of chimeric receptors in which sequence of intracellular loop 2 was substituted indicated that the nature of amino acids in this domain may indirectly modulate A_2aAR-G_s coupling. Replacement of the cytoplasmic tail of the A_2aAR with the A₁AR tail did not affect adenylyl cyclase stimulation. Thus, selective activation of G_s is predominantly dictated by the NH₂-terminal segment of the third intracellular loop of the A_2aAR.

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