Editors' ChoicePharmacology

β-Blockers: Both Antagonist and Agonist

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Science Signaling  30 Sep 2008:
Vol. 1, Issue 39, pp. ec336
DOI: 10.1126/scisignal.139ec336

The class of drugs called β-blockers is used to treat high blood pressure and various heart disorders. There is variation in the clinical efficacy of these drugs, and Kim et al. found that two of 20 β-blockers that they screened served as both antagonists and agonists at β1-adrenergic receptors (β1-ARs), the molecular target of these drugs. β1-ARs are G protein-coupled receptors (GPCRs), and all β-blockers inhibit signaling by the receptor to the cognate G protein. However, β-ARs can signal not only through G proteins but also through interactions with β-arrestins, which are scaffolding proteins that interact with the receptors after receptor phosphorylation by GPCR-coupled receptor kinase (GRK). Kim et al. found that in addition to their antagonist activity, alprenolol (Alp) and carvedilol (Car) stimulated β1-AR-mediated activation of the epidermal growth factor receptor (EGFR) and activation of extracellular signal-regulated kinase (ERK). Activation of EGFR was detected by monitoring internalization of a tagged version of EGFR (GFP-EGFR) in cells transfected with β1-AR and GFP-EGFR; EGFR and ERK phosphorylation was also stimulated by Alp and Car. Cells expressing a form of β1-AR in which the GRK phosphorylation sites were mutated did not exhibit activation of EGFR in response to Alp or Car. Knockdown of β-arrestin 1, β-arrestin 2, or both by siRNA also blocked activation of ERK by Alp or Car. β1-AR-mediated activation of EGFR is known to involve the protein tyrosine kinase Src and activation of matrix metalloproteinase (MMP) to release EGF. EGFR and ERK activation mediated by Alp or Car was inhibited when either Src or MMP activity was pharmacologically inhibited. Importantly, the authors extended their findings obtained in transfected cells to mice and showed that infusion of Alp or Car stimulated ERK phosphorylation in the heart and that this response was blocked if MMP or EGFR activity was pharmacologically inhibited. The therapeutic benefits of these drugs may be the result of their dual activities--inhibition of G protein signaling and promotion of β-arrestin-mediated signaling, which activates a pathway that has been implicated in cardioprotective effects of β1-AR signaling.

I.-M. Kim, D. G. Tilley, J. Chen, N. C. Salazar, E. J. Whalen, J. D. Violin, H. A. Rockman, β-blockers alprenolol and carvedilol stimulate β-arrestin-mediated EGFR transactivation. Proc. Natl. Acad. Sci. U.S.A. 105, 14555-14560 (2008). [Abstract] [Full Text]