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Evidence for Pleiotropic Signaling at the Mouse β 3 -Adrenoceptor Revealed by SR59230A [3-(2-Ethylphenoxy)-1-[(1, S )-1,2,3,4-tetrahydronapth-1-ylamino]-2 S -2-propanol Oxalate]

2004; American Society for Pharmacology and Experimental Therapeutics; Volume: 312; Issue: 3 Linguagem: Inglês

10.1124/jpet.104.076901

1521-0103

Dana S. Hutchinson, Masaaki Sato, Bronwyn A. Evans, Arthur Christopoulos, Roger J. Summers,

Stress Responses and Cortisol

This study examines the action of the β 3 -adrenoceptor antagonist SR59230A [3-(2-ethylphenoxy)-1-[(1, S )-1,2,3,4-tetrahydronapth-1-ylamino]-2 S -2-propanoloxalate] at cloned mouse β 3 -adrenoceptors expressed in Chinese hamster ovary cells (CHO-K1-β 3 ) or endogenously expressed in 3T3-F442A adipocytes or ileum. SR59230A displayed partial agonist properties compared with the β 3 -adrenoceptor agonist CL316243 [( R,R )-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]-amino]-propyl]1,3-benzodioxole-2,2-dicarboxylate] in CHO-K1-β 3 with the intrinsic activity increasing with the level of receptor expression. Functional affinity values for SR59230A at each level of receptor expression were in agreement with p K I values determined by binding. In cytosensor microphysiometer studies, SR59230A was a full agonist for increases in extracellular acidification rates (ECARs) at all levels of receptor expression, and antagonist actions were measurable only in medium- or low-expressing cells. In 3T3-F442A adipocytes, SR59230A antagonized CL316243-mediated increases of cAMP and had no agonist actions. However, in the cytosensor micro-physiometer, SR59230A (acting via β 3 -adrenoceptors) was an agonist with an intrinsic activity greater than CL316243. In mouse ileum, SR59230A relaxed smooth muscle, although concentration-response curves were biphasic. Relaxant effects were produced by concentrations that did not affect cAMP levels. Differences in tissue responses to SR59230A were not caused by major differences in expression of Gαs. ECAR responses were not affected by pretreatment of cells with pertussis toxin, indicating that signaling did not involve Gi. Therefore, SR59230A displays agonist and antagonist actions at the mouse β 3 -adrenoceptor. Because SR59230A only antagonized accumulation of cAMP in 3T3-F442A adipocytes yet in the same cells was an agonist for ECAR, cAMP-independent signaling pathways must mediate part of the agonist actions in the microphysiometer.