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Sci. Signal., 9 August 2011
Vol. 4, Issue 185, p. ra53
[DOI: 10.1126/scisignal.2001681]

RESEARCH ARTICLES

A Polymorphism-Specific "Memory" Mechanism in the β2-Adrenergic Receptor

Andrea Ahles1,2, Francesca Rochais2,3, Torsten Frambach4, Moritz Bünemann5,6, and Stefan Engelhardt1,2,7*

1 Institute of Pharmacology and Toxicology, Technische Universitaet Muenchen (TUM), Biedersteiner Strasse 29, 80802 Munich, Germany.
2 Rudolf Virchow Center, Deutsche Forschungsgemeinschaft Research Center for Experimental Biomedicine, Universitaet Wuerzburg, 97078 Wuerzburg, Germany.
3 Developmental Biology Institute, Université de la Méditerranée, 13000 Marseille, France.
4 Department of Obstetrics and Gynecology, Universitaet Wuerzburg, 97078 Wuerzburg, Germany.
5 Institute of Pharmacology and Clinical Pharmacy, Universitaet Marburg, 35032 Marburg, Germany.
6 Institute of Pharmacology and Toxicology, Universitaet Wuerzburg, 97078 Wuerzburg, Germany.
7 Munich Heart Alliance, 80802 Munich, Germany.

Abstract: Signaling through G protein (heterotrimeric guanosine triphosphate–binding protein)–coupled receptors is affected by polymorphisms in receptor-encoding genes. Using fluorescence resonance energy transfer, we found that the β2-adrenergic receptor (β2AR) responded to repeated activation with altered activation kinetics. Polymorphic variants of the β2AR displayed divergent changes of β2AR activation kinetics that closely mimicked their different efficacies to generate cyclic adenosine 3',5'-monophosphate. More efficacious variants became faster in their activation kinetics, whereas less efficacious variants became slower, compared to their initial activation. These differences depended on phosphorylation of the receptor by G protein–coupled receptor kinases. Our findings suggest an intrinsic, polymorphism-specific property of the β2AR that alters activation kinetics upon continued stimulation and that may account for individual drug responses.

* To whom correspondence should be addressed. E-mail: stefan.engelhardt{at}tum.de

Citation: A. Ahles, F. Rochais, T. Frambach, M. Bünemann, S. Engelhardt, A Polymorphism-Specific "Memory" Mechanism in the β2-Adrenergic Receptor. Sci. Signal. 4, ra53 (2011).

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