We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Conserved structural, pharmacological and functional properties among the three human and five zebrafisha<sub>2</sub>-adrenoceptors.
- Authors
Ruuskanen, Jori O.; Laurila, Jonne; Xhaard, Henri; Rantanen, Ville-Veikko; Vuoriluoto, Karoliina; Wurster, Siegfried; Marjamäki, Anne; Vainio, Minna; Johnson, Mark S.; Scheinin, Mika
- Abstract
Zebrafish has five distincta2-adrenoceptors. Two of these,a2Da anda2Db, represent a duplicated, fourtha2-adrenoceptor subtype, while the others are orthologue of the humana2A-,a2B- anda2C-adrenoceptors. Here, we have compared the pharmacological properties of these receptors to infer structural determinants of ligand interactions.The zebrafisha2-adrenoceptors were expressed in Chinese hamster ovary cells and tested in competitive ligand binding assays and in a functional assay (agonist-stimulated[35S]GTP?S binding). The affinity results were used to cluster the receptors and, separately, the ligands using both principal component analysis and binary trees.The overall ligand binding characteristics, the order of potency and efficacy of the tested agonists and the G-protein coupling of the zebrafish and humana2-adrenoceptors, separated by~350 million years of evolution, were found to be highly conserved. The binding affinities of the 20 tested ligands towards the zebrafisha2-adrenoceptors are generally comparable to those of their human counterparts, with a few compounds showing up to 40-fold affinity differences.Thea2A orthologues and the zebrafisha2D duplicates clustered as close pairs, but the relationships between the orthologues ofa2B anda2C were not clearly defined. Applied to the ligands, our clustering methods segregated the ligands based on their chemical structures and functional properties. As the ligand binding pockets formed by the transmembrane helices show only minor differences among thea2-adrenoceptors, we suggest that the second extracellular loop-where significant sequence variability is located-might contribute significantly to the observed affinity differences.British Journal of Pharmacology (2005) 144, 165-177. doi:10.1038/sj.bjp.0706057 Published online 10 January 2005
- Subjects
ADRENERGIC receptors; CELLS; PHARMACOLOGY; ZEBRA danio; BIOCHEMISTRY; DRUG receptors
- Publication
British Journal of Pharmacology, 2005, Vol 144, Issue 2, p165
- ISSN
0007-1188
- Publication type
Article
- DOI
10.1038/sj.bjp.0706057