Novel mutants of the human beta1-adrenergic receptor reveal amino acids relevant for receptor activation

The Journal of Biological Chemistry
Björn BehrKarl-Norbert Klotz

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-...Continue Reading

References

Nov 1, 1987·Proceedings of the National Academy of Sciences of the United States of America·T FrielleB K Kobilka
Apr 24, 1987·Nucleic Acids Research·P R SchofieldE G Peralta
Dec 5, 1993·Journal of Molecular Biology·A Sali, T L Blundell
Aug 20, 1996·Proceedings of the National Academy of Sciences of the United States of America·K WielandM J Lohse
Nov 18, 1998·Current Opinion in Structural Biology·R A LaskowskiJ M Thornton
Jan 15, 1999·Pharmacology & Therapeutics·J Wess
Feb 3, 1999·Bioinformatics·J A CuffG J Barton
Apr 23, 1999·The Journal of Biological Chemistry·D A MasonS B Liggett
Sep 3, 1999·FEBS Letters·A LattionS Cotecchia
Dec 11, 1999·Nucleic Acids Research·H M BermanP E Bourne
Aug 5, 2000·Science·K PalczewskiM Miyano
Aug 15, 2000·Annual Review of Biophysics and Biomolecular Structure·M A Martí-RenomA Sali
Oct 25, 2000·Protein Science : a Publication of the Protein Society·A FiserA Sali
Jan 25, 2002·Annual Review of Pharmacology and Toxicology·Lei Shi, Jonathan A Javitch
Jun 19, 2002·Protein Science : a Publication of the Protein Society·Csaba Hetényi, David van der Spoel
Oct 16, 2003·The Journal of Biological Chemistry·Gayathri SwaminathBrian K Kobilka
Jan 6, 2004·Proceedings of the National Academy of Sciences of the United States of America·Lei Shi, Jonathan A Javitch
Apr 23, 2004·Molecular Pharmacology·Brian Kobilka
Mar 16, 2005·Nature Structural & Molecular Biology·Jeffery M KlcoThomas J Baranski

❮ Previous
Next ❯

Citations

Oct 10, 2006·Naunyn-Schmiedeberg's Archives of Pharmacology·Nadja NiclaussMartin C Michel
Aug 23, 2007·Journal of Computer-aided Molecular Design·Andrea Strasser, Hans-Joachim Wittmann
Feb 2, 2008·The Biochemical Journal·Doreen ThorTorsten Schöneberg
Jul 19, 2013·Journal of Medicinal Chemistry·Marvin A Soriano-UrsúaSantiago Vilar

❮ Previous
Next ❯

Related Concepts

Related Feeds

Adrenergic Receptors: Trafficking

Adrenergic receptor trafficking is an active physiological process where adrenergic receptors are relocated from one region of the cell to another or from one type of cell to another. Discover the latest research on adrenergic receptor trafficking here.

ASBMB Publications

The American Society for Biochemistry and Molecular Biology (ASBMB) includes the Journal of Biological Chemistry, Molecular & Cellular Proteomics, and the Journal of Lipid Research. Discover the latest research from ASBMB here.