title: Evidence for a secondary state of the human beta3-adrenoceptor.
abstract: There are three members of the beta-adrenoceptor family, all of which are primarily coupled to G(s) proteins. Recent studies using the huge range of beta-ligands now available have given remarkable new insights into their pharmacology. beta1-adrenoceptors exist in at least two active conformations, whereas beta2-adrenoceptors are able to induce signaling via different agonist-induced receptor conformational states, and their affinity for antagonists can be altered by highly efficacious agonists. This study therefore examined the pharmacology of the human beta3-adrenoceptor stably expressed in Chinese hamster ovary cells. Several compounds described previously as beta-antagonists have agonist properties at the beta3-adrenoceptor. Antagonist affinity measurements varied at the beta3-adrenoceptor in a manner similar to those observed at human beta1-adrenoceptors and unlike those seen at beta2-adrenoceptors. Some ligands (e.g., fenoterol and cimaterol) were more readily inhibited by all antagonists, whereas other ligands [e.g., alprenolol and 1-(2-ethylphenoxy)-3-[[(1S)-1,2,3,4-tetrahydro-1-naphthalenyl]amino]-(2S)-2-propanol hydrochloride [SR 59230A]) stimulated responses that were more resistant to antagonism. Alprenolol inhibited fenoterol-induced beta3-adrenoceptor responses while acting as an agonist at higher concentrations. This is highly suggestive of two active conformational states of the beta3-adrenoceptor. (S)-4-[2-Hydroxy-3-phenoxypropylaminoethoxy]-N-(2-methoxyethyl)phenoxyacetamide (ZD 7114) stimulated a two-component response, of which the first component was more readily antagonized than the second. Taken together, these experiments suggest that the human beta3-adrenoceptor exists in at least two different agonist conformations with a similar high- and low-affinity pharmacology analogous to, if not as pronounced as, the beta1-adrenoceptor. Both conformations are present in living cells and can be distinguished by their pharmacological characteristics. In this respect, the human beta3-adrenoceptor seems similar to the human beta1-adrenoceptor.
authors.affiliation: Institute of Cell Signaling, Medical School, University of Nottingham, Queen's Medical Centre, Nottingham, NG7 2UH, United Kingdom. jillian.baker@nottingham.ac.uk
authors.forename: Jillian G
authors.initials: JG
authors.lastname: Baker
mesh_terms: D058667:Adrenergic beta-3 Receptor Agonists; D058673:Adrenergic beta-3 Receptor Antagonists; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008024:Ligands; D011487:Protein Conformation; D022702:Receptors, Adrenergic, beta-3 / Q000737:chemistry* / Q000235:genetics; D014162:Transfection
chemical_list: D058667:Adrenergic beta-3 Receptor Agonists; D058673:Adrenergic beta-3 Receptor Antagonists; D008024:Ligands; D022702:Receptors, Adrenergic, beta-3; D000242:Cyclic AMP