ADENYLYL-CYCLASE STIMULATION BY THE HUMAN AND RAT BETA(3) ADRENERGIC-RECEPTOR ISOFORMS EXPRESSED IN THE CHO CELL

Objectives and method. - The beta(3) adrenergic receptor stimulates li polysis and colonic relaxation in the rat, and, suggestively, in man. Several human forms generated by differents mRNA splicings can occur: the A form of 396 aminoacids and the B and C forms extended by 12 and 6 aminoacids respectively, in the C-terminus region. In order to chara cterize these differents forms as expressed in CHO cells, we studied a denylyl cyclase stimulation by the beta(3) agonists, SR58611A and BRL3 7344 and its inhibition by the beta(3) antagonist SR59230. Results. - This antagonist totally inhibited SR58611-adenylyl cyclase stimulation with the following hie rarchy of potency: C form much greater than B > A. In rat, a unique form is expressed which is close to the human B form. This form was the less sensitive to beta(1) and beta(2) antagoni sts. Conclusion. - These findings constitute a molecular pharmacologic al basis for the design of beta(3) agonists of therapeutic value.