TY - JOUR T1 - Agonist Interactions with Chimeric and Mutant β<sub>1</sub>- and β<sub>3</sub>-Adrenergic Receptors: Involvement of the Seventh Transmembrane Region in Conferring Subtype Specificity JF - Molecular Pharmacology JO - Mol Pharmacol SP - 856 LP - 861 VL - 53 IS - 5 AU - James G. Granneman AU - Kristine N. Lahners AU - Ying Zhai Y1 - 1998/05/01 UR - http://molpharm.aspetjournals.org/content/53/5/856.abstract N2 - β1- and β3-adrenergic receptors (AR) are the predominant β-AR subtypes in adipocytes, and analysis of native and recombinant β-AR has revealed several pharmacological and biochemical differences between these subtypes. This study used chimeric and mutated rat β-AR expressed in Chinese hamster ovary cells to examine the basis of certain characteristic differences in the agonist properties of catecholamines and prototypic β3-AR agonists. The exchange of sequence beyond transmembrane (TM) region 6 between the β-AR subtypes had dramatic and reciprocal effects on the affinity and efficacy of the prototypic β3-AR agonists BRL 37,344 and CL 316,243, without affecting the interactions with catecholamines. Mutation of Phe350 and Phe351 in TM7 of the β1-AR to Ala and Leu found in the β3-AR was sufficient to allow activation by prototypic β3-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 β3-AR agonists. β1-AR containing β3-AR sequence from predicted TM5 through TM6 exhibited reduced affinity for catecholamines without altering agonist potency, suggesting enhanced coupling efficiency. Inclusion of the homologous β1-AR sequence in the β3-AR, however, did not produce reciprocal effects. These results are the first to define a major determinant of β3-AR subtype-selective agonism in TM7 and demonstrate that the determinants of selective phenethanolamines, catecholamines, and propranolol action are distinct. The American Society for Pharmacology and Experimental Therapeutics ER -