Abstract
β-Adrenergic and angiotensin II type 1A receptors are therapeutic targets for the treatment of a number of common human diseases. Pharmacological agents designed as antagonists for these receptors have positively affected the morbidity and mortality of patients with hypertension, heart failure, and renal disease. Antagonism of these receptors, however, may only partially explain the therapeutic benefits of β-blockers and angiotensin receptor blockers given the emerging concept of functional selectivity or biased agonism. This new pharmacological paradigm suggests that multiple signaling pathways can be differentially modified by a single ligand-receptor interaction. This review examines the functional selectivity of β-adrenergic and angiotensin II type 1A receptors with respect to their ability to signal via both G protein-dependent and G protein-independent mechanisms, with a focus on the multifunctional protein β-arrestin. Also highlighted are the concept of “biased signaling” through β-arrestin mediated pathways, the affect of ligand/receptor modification on such biased agonism, and the implications of functional selectivity for the development of the next generation of β-blockers and angiotensin receptor blockers.
Footnotes
This work was supported in part by National Institutes of Health National Heart, Lung, and Blood Institute [Grants HL075443, HL56687]; and a Duke University Medical School Stead Fellowship.
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.110.067066.
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ABBREVIATIONS:
- βAR
- β-adrenergic receptor
- AT1aR
- angiotensin II type 1a receptor
- GRK
- G protein-coupled receptor kinase
- ERK
- extracellular-signal receptor kinase
- EGFR
- epidermal growth factor receptor
- MAP
- mitogen-activated protein
- siRNA
- small interfering RNA
- AngII
- angiotensin II
- FRET
- fluorescence resonance energy transfer
- ARB
- angiotensin receptor blocker
- CaMKII
- Ca2+/calmodulin kinase II
- PKC
- protein kinase C
- Epac
- cAMP-dependent guanine nucleotide exchange factor
- GPCR
- G protein-coupled receptor
- R031-8425
- 2-[8-(aminomethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-3-yl]-3-(1-methylindol-3-yl)maleimide.
- Received June 19, 2010.
- Accepted September 15, 2010.
- Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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