Real-time optical recording of beta1-adrenergic receptor activation reveals supersensitivity of the Arg389 variant to carvedilol

J Clin Invest. 2007 Jan;117(1):229-35. doi: 10.1172/JCI30012.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-Antagonists / pharmacology*
  • Amino Acid Substitution
  • Arginine*
  • Base Sequence
  • Carbazoles / pharmacology*
  • Carvedilol
  • Cell Line
  • Fluorescence Resonance Energy Transfer
  • Genetic Variation*
  • Propanolamines / pharmacology*
  • Receptors, Adrenergic, beta-1 / drug effects
  • Receptors, Adrenergic, beta-1 / genetics*
  • Receptors, Adrenergic, beta-1 / physiology*
  • Recombinant Proteins / drug effects
  • Recombinant Proteins / metabolism
  • Transfection


  • Adrenergic beta-Antagonists
  • Carbazoles
  • Propanolamines
  • Receptors, Adrenergic, beta-1
  • Recombinant Proteins
  • Carvedilol
  • Arginine