http://www.cnr.it/ontology/cnr/individuo/prodotto/ID17451

Novel mutants of the human beta(1)-adrenergic receptor reveal amino acids relevant for receptor activation (Articolo in rivista)

Type

Prodotto della ricerca (Classe)
Articolo in rivista (Classe)

Label

Novel mutants of the human beta(1)-adrenergic receptor reveal amino acids relevant for receptor activation (Articolo in rivista) (literal)

Anno

2006-01-01T00:00:00+01:00 (literal)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi

10.1074/jbc.M601791200 (literal)

Alternative label

Behr B., Hoffmann C., Ottolina G., Klotz K.N. (2006)
Novel mutants of the human beta(1)-adrenergic receptor reveal amino acids relevant for receptor activation
in The Journal of biological chemistry (Print); American Society Of Biochemistry And Molecular Biology Inc. (ASBMB), Rockville (Stati Uniti d'America)
(literal)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori

Behr B., Hoffmann C., Ottolina G., Klotz K.N. (literal)

Pagina inizio

18120 (literal)

Pagina fine

18125 (literal)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#url

http://www.jbc.org/content/281/26/18120 (literal)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroVolume

281 (literal)

Rivista

?The ?Journal of biological chemistry (Rivista)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroFascicolo

26 (literal)

Note

ISI Web of Science (WOS) (literal)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni

Univ Wurzburg, Inst Pharmakol & Toxikol, D-97078 Wurzburg, Germany CNR, Ist Chim Riconoscimento Mol, I-20131 Milan, Italy (literal)

Titolo

Novel mutants of the human beta(1)-adrenergic receptor reveal amino acids relevant for receptor activation (literal)

Abstract

Activation of G protein-coupled receptors like the beta(1)-adrenergic receptor results in conformational changes that ultimately lead to signal propagation through a G protein to an effector like adenylyl cyclase. In this study we identified amino acids that seem to be critical for activation of the human beta(1)-adrenergic receptor. Activation patterns of mutant receptors were analyzed using two structurally different ligands for beta-adrenergic receptors that both are mixed agonist/antagonists. Broxaterol and terbutaline are agonists at beta(2)- and beta(3)-receptors; however, they act as antagonists at the beta(1)-subtype. We reasoned that this functional selectivity may be reflected by a corresponding sequence pattern in the receptor subtypes. Therefore, we exchanged single amino acids of the beta(1)-adrenergic receptor for residues that were identical in the beta(2)- and beta(3)-subtypes but different in the beta(1)-receptor. Pharmacological characterization of such receptor mutants revealed that binding of a panel of agonists and antagonists including broxaterol and terbutaline was unaltered. However, two of the mutants (I185V and D212N) were activated by broxaterol and terbutaline, which acted as antagonists at the wild-type receptor. Two additional mutants (V120L and K253R) could be activated by terbutaline alone, which is structurally more closely related to endogenous catecholamines like epinephrine than to broxaterol. A model of the human beta(1)-adrenergic receptor showed that the four gain-of-function mutations are outside of the putative ligand-binding domain substantiating the lack of an effect of the mutations on binding characteristics. These results support the notion that Val-120, Ile-185, Asp-212, and Lys-253 are critically involved in conformational changes occurring during receptor activation. (literal)

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