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Teaching old receptors new tricks: biasing seven-transmembrane receptors

Key Points

  • Seven-transmembrane receptors (7TMRs), also known as G protein-couple receptors, are the largest class of transmembrane receptors and a common target for therapeutics. Initially thought to signal only through heterotrimeric G proteins, it is now recognized that they also signal through the multifunctional adapter proteins β-arrestin 1 and β-arrestin 2.

  • β-arrestin-mediated signalling can have distinct functional consequences from G protein-mediated signalling. G protein-mediated signalling is usually accomplished via the generation of second messengers that signal to downstream partners. By contrast, β-arrestin-mediated signalling usually results in the formation of signalling complexes scaffolded by β-arrestins that lead to activation of kinases and other downstream targets.

  • Biased agonists are capable of signalling through only a restricted subset of all of the pathways usually available to the receptor. β-arrestin-biased agonists act as agonists for β-arrestin-mediated signalling and as weak partial agonists or antagonists of G protein-mediated signalling.

  • In many systems, receptor activation by β-arrestin-biased agonists results in functionally distinct responses from activation by non-biased agonists. For example, a β-arrestin-biased agonist of the parathyroid hormone receptor is capable of stimulating trabecular bone growth in mice without increasing bone resorption, whereas an unbiased full agonist stimulates both bone growth and resorption.

  • Cell-based assays used to facilitate the discovery of β-arrestin-biased agonists may be based on redistribution of labelled receptor or β-arrestin; proximity between receptor and β-arrestin; conformation of receptor or β-arrestin; or activation of downstream signalling pathways known to be regulated selectively by β-arrestins. Most of these assays have been adapted for high-throughput screening.

  • As we learn more about β-arrestin-mediated signalling at other 7TMRs, new targets for the development of β-arrestin-biased agonists will undoubtedly arise. Thus, it is important that we continue to focus on studying the physiological impact of β-arrestin-mediated signaling in cell-based and animal studies.


Seven-transmembrane receptors (7TMRs; also known as G protein-coupled receptors) are the largest class of receptors in the human genome and are common targets for therapeutics. Originally identified as mediators of 7TMR desensitization, β-arrestins (arrestin 2 and arrestin 3) are now recognized as true adaptor proteins that transduce signals to multiple effector pathways. Signalling that is mediated by β-arrestins has distinct biochemical and functional consequences from those mediated by G proteins, and several biased ligands and receptors have been identified that preferentially signal through either G protein- or β-arrestin-mediated pathways. These ligands are not only useful tools for investigating the biochemistry of 7TMR signalling, they also have the potential to be developed into new classes of therapeutics.

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Figure 1: G protein and β-arrestin-mediated signalling.
Figure 2: Biased ligands and biased receptors.
Figure 3: Quantifying the pluridimensional efficacies of seven-transmembrane receptors.
Figure 4: Assays for β-arrestin recruitment and activation.


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We thank E. Whalen, J. Violin, S. Ahn and A. Shukla for critical review of the manuscript. We thank D. Addison and E. Hall for secretarial assistance. This work was supported in part by National Institutes of Health (NIH) Grants HL16037 and HL70631 to R.J.L. R.J.L. is an Investigator with the Howard Hughes Medical Institute. S.R. is supported by NIH T32 training grant HL07101-34.

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Correspondence to Robert J. Lefkowitz.

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Robert J. Lefkowitz is a co-founder of Trevena, a company that is developing drugs to target seven transmembrane receptors.

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G protein

A heterotrimeric protein that exchanges GDP for GTP in its α-subunit on agonist binding to a seven-transmembrane receptor, resulting in dissociation of the complex into Gα and Gβγ subunits. These subunits lead to the activation of second messenger systems through the regulation of enzymes such as adenylyl cyclase or phospholipase C.


Multifunctional adaptor proteins that are important in regulating desensitization and signalling by seven-transmembrane receptors and other transmembrane receptors.


A multifunctional adaptor protein. One of its roles includes the regulation of TCF/LEF transcription factors in response to signalling by Wnts through the frizzled seven-transmembrane receptors.


The activation of a transmembrane receptor that results from signalling caused by activation of another receptor. In the case of epidermal growth factor receptor (EGFR) transactivation, agonist binding at a number of seven-transmembrane receptors activates a pathway that releases a membrane-bound EGF ligand by proteolytic cleavage, which then activates the EGFR.

Biased agonist

A ligand that results in the activation of select, but not all, available signalling pathways that are known to be activated by the receptor.

Positive inotropes

An agent that increases the force of the heart's contraction. Negative inotropes decrease the force of contraction.


A term that is commonly used to refer broadly to neutral antagonists, weak partial agonists and inverse agonists.

Partial agonist

A ligand that when bound to a receptor results in a submaximal response. Partial agonists can antagonize full agonists.

Inverse agonist

A ligand that decreases the signalling activity of the receptor on binding compared with the ligand-unbound state.

Neutral antagonist

A ligand that results in no change in activity of the receptor on binding compared with the ligand-unbound state.

Allosteric site

A binding site on a seven-transmembrane receptor that is different than the orthosteric site.

Orthosteric site

The binding site on a seven-transmembrane receptor to which the endogenous agonist binds.

Allosteric modulator

A ligand that binds to the allosteric site of the receptor and affects receptor responses to orthosteric ligands. Some allosteric modulators are capable of generating biased responses.


Relates to the relaxation and filling of the heart. Positive lusitropic agents improve the heart's relaxation and filling.

Full agonist

A ligand that completely activates the receptor on binding.

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Rajagopal, S., Rajagopal, K. & Lefkowitz, R. Teaching old receptors new tricks: biasing seven-transmembrane receptors. Nat Rev Drug Discov 9, 373–386 (2010).

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