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.
Users
Please
log in to take part in the discussion (add own reviews or comments).