title: Real-time optical recording of beta1-adrenergic receptor activation reveals supersensitivity of the Arg389 variant to carvedilol.
abstract: Antagonists of beta-adrenergic receptors (beta-ARs) have become a main therapeutic regimen for the treatment of heart failure even though the mechanisms of their beneficial effects are still poorly understood. Here, we used fluorescent resonance energy transfer-based (FRET-based) approaches to directly monitor activation of the beta(1)-AR and downstream signaling. While the commonly used beta-AR antagonists metoprolol, bisoprolol, and carvedilol displayed varying degrees of inverse agonism on the Gly389 variant of the receptor (i.e., actively switching off the beta(1)-AR), surprisingly, only carvedilol showed very specific and marked inverse agonist effects on the more frequent Arg389 variant. These specific effects of carvedilol on the Arg389 variant of the beta(1)-AR were also seen for control of beating frequency in rat cardiac myocytes expressing the 2 receptor variants. This FRET sensor permitted direct observation of activation of the beta(1)-AR in living cells in real time. It revealed that beta(1)-AR variants dramatically differ in their responses to diverse beta blockers, with possible consequences for their clinical use.
authors.affiliation: Rudolf-Virchow-Center, DFG-Research Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany.
authors.forename: Francesca
authors.initials: F
authors.lastname: Rochais
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Vilardaga
authors.forename: Viacheslav O
authors.initials: VO
authors.lastname: Nikolaev
authors.forename: Moritz
authors.initials: M
authors.lastname: Bünemann
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Lohse
authors.forename: Stefan
authors.initials: S
authors.lastname: Engelhardt
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D019943:Amino Acid Substitution; D001120:Arginine; D001483:Base Sequence; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D002460:Cell Line; D031541:Fluorescence Resonance Energy Transfer; D014644:Genetic Variation; D011412:Propanolamines / Q000494:pharmacology*; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects / Q000235:genetics* / Q000502:physiology*; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D014162:Transfection
chemical_list: D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D011412:Propanolamines; D018342:Receptors, Adrenergic, beta-1; D011994:Recombinant Proteins; D000077261:Carvedilol; D001120:Arginine