RT Journal Article
SR Electronic
T1 Evidence for a Secondary State of the Human β3-Adrenoceptor
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1645
OP 1655
DO 10.1124/mol.105.015461
VO 68
IS 6
A1 Jillian G. Baker
YR 2005
UL http://molpharm.aspetjournals.org/content/68/6/1645.abstract
AB There are three members of the β-adrenoceptor family, all of which are primarily coupled to Gs proteins. Recent studies using the huge range of β-ligands now available have given remarkable new insights into their pharmacology. β1-adrenoceptors exist in at least two active conformations, whereas β2-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 β3-adrenoceptor stably expressed in Chinese hamster ovary cells. Several compounds described previously as β-antagonists have agonist properties at the β3-adrenoceptor. Antagonist affinity measurements varied at the β3-adrenoceptor in a manner similar to those observed at human β1-adrenoceptors and unlike those seen at β2-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 β3-adrenoceptor responses while acting as an agonist at higher concentrations. This is highly suggestive of two active conformational states of the β3-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 β3-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 β1-adrenoceptor. Both conformations are present in living cells and can be distinguished by their pharmacological characteristics. In this respect, the human β3-adrenoceptor seems similar to the human β1-adrenoceptor.