QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.104.076901v1 312/3/1064    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hutchinson, D. S. Articles by Summers, R. J. Search for Related Content PubMed PubMed Citation Articles by Hutchinson, D. S. Articles by Summers, R. J.

CELLULAR AND MOLECULAR

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

Department of Pharmacology, Monash University, Victoria, Australia (D.S.H., M.S., B.A.E., R.J.S.); and Department of Pharmacology, University of Melbourne, Parkville, Victoria, Australia (A.C.)

This study examines the action of the ₃-adrenoceptor antagonist SR59230A [3-(2-ethylphenoxy)-1-[(1,S)-1,2,3,4-tetrahydronapth-1-ylamino]-2S-2-propanoloxalate] at cloned mouse ₃-adrenoceptors expressed in Chinese hamster ovary cells (CHO-K1-₃) or endogenously expressed in 3T3-F442A adipocytes or ileum. SR59230A displayed partial agonist properties compared with the ₃-adrenoceptor agonist CL316243 [(R,R)-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]-amino]-propyl]1,3-benzodioxole-2,2-dicarboxylate] in CHO-K1-₃ 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 pK_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 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 Gs. 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 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.

Address correspondence to: Dr. Roger J. Summers, Department of Pharmacology, P.O. Box 13E, Monash University, Victoria 3800, Australia. E-mail: roger.summers{at}med.monash.edu.au

This article has been cited by other articles:

				M. Sato, D. S. Hutchinson, B. A. Evans, and R. J. Summers Mol. Pharmacol., November 1, 2008; 74(5): 1417 - 1428. [Abstract] [Full Text] [PDF]

				M. Sato, T. Horinouchi, D. S. Hutchinson, B. A. Evans, and R. J. Summers Ligand-Directed Signaling at the beta3-Adrenoceptor Produced by 3-(2-Ethylphenoxy)-1-[(1,S)-1,2,3,4-tetrahydronapth-1-ylamino]-2S-2-propanol oxalate (SR59230A) Relative to Receptor Agonists Mol. Pharmacol., November 1, 2007; 72(5): 1359 - 1368. [Abstract] [Full Text] [PDF]

				A. Hicks, G. P. McCafferty, E. Riedel, N. Aiyar, M. Pullen, C. Evans, T. D. Luce, R. W. Coatney, G. C. Rivera, T. D. Westfall, et al. GW427353 (Solabegron), a Novel, Selective beta3-Adrenergic Receptor Agonist, Evokes Bladder Relaxation and Increases Micturition Reflex Threshold in the Dog J. Pharmacol. Exp. Ther., October 1, 2007; 323(1): 202 - 209. [Abstract] [Full Text] [PDF]

				M. Sato, D. S. Hutchinson, T. Bengtsson, A. Floren, U. Langel, T. Horinouchi, B. A. Evans, and R. J. Summers Functional Domains of the Mouse {beta}3-Adrenoceptor Associated with Differential G Protein Coupling J. Pharmacol. Exp. Ther., December 1, 2005; 315(3): 1354 - 1361. [Abstract] [Full Text] [PDF]

				J. G. Baker Evidence for a Secondary State of the Human {beta}3-Adrenoceptor Mol. Pharmacol., December 1, 2005; 68(6): 1645 - 1655. [Abstract] [Full Text] [PDF]