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Vol. 53, Issue 5, 856-861, May 1998

Agonist Interactions with Chimeric and Mutant beta 1- and beta 3-Adrenergic Receptors: Involvement of the Seventh Transmembrane Region in Conferring Subtype Specificity

James G. Granneman, Kristine N. Lahners, and Ying Zhai

Cellular and Clinical Neurobiology Program, Department of Psychiatry and Behavioral Neuroscience, Wayne State University School of Medicine Detroit, Michigan 48201

beta 1- and beta 3-adrenergic receptors (AR) are the predominant beta -AR subtypes in adipocytes, and analysis of native and recombinant beta -AR has revealed several pharmacological and biochemical differences between these subtypes. This study used chimeric and mutated rat beta -AR expressed in Chinese hamster ovary cells to examine the basis of certain characteristic differences in the agonist properties of catecholamines and prototypic beta 3-AR agonists. The exchange of sequence beyond transmembrane (TM) region 6 between the beta -AR subtypes had dramatic and reciprocal effects on the affinity and efficacy of the prototypic beta 3-AR agonists BRL 37,344 and CL 316,243, without affecting the interactions with catecholamines. Mutation of Phe350 and Phe351 in TM7 of the beta 1-AR to Ala and Leu found in the beta 3-AR was sufficient to allow activation by prototypic beta 3-AR agonists. Interestingly, this mutation did not affect catecholamine action and it did not impair the ability of propranolol to block the actions of isoproterenol or the selective beta 3-AR agonists. beta 1-AR containing beta 3-AR sequence from predicted TM5 through TM6 exhibited reduced affinity for catecholamines without altering agonist potency, suggesting enhanced coupling efficiency. Inclusion of the homologous beta 1-AR sequence in the beta 3-AR, however, did not produce reciprocal effects. These results are the first to define a major determinant of beta 3-AR subtype-selective agonism in TM7 and demonstrate that the determinants of selective phenethanolamines, catecholamines, and propranolol action are distinct.

Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


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