β-Arrestin-biased ligands at seven-transmembrane receptors

Violin, Jonathan D.; Lefkowitz, Robert J.

doi:10.1016/j.tips.2007.06.006

Cited by 546 publications

(474 citation statements)

References 43 publications

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“…These findings suggest that DOI activates 5-HT2AR signaling pathways that do not require ␤-arrestins and that DOI- induced head twitches are mediated by ␤-arrestin-2-independent pathways. ␤-arrestins have been shown to mediate ERK1/2 activation by some GPCRs (2,30). Our data suggest that the 5-HT2AR is among these receptors.…”

Section: Discussionmentioning

confidence: 53%

“…The growing body of evidence supports a model wherein GPCR regulation and subsequent signaling are determined by proteins that interact with the receptor within distinct cellular environments (1,2). Moreover, the chemical nature of the ligand can dictate the receptor's ability to recruit and interact with such proteins and can thereby determine the extent of overall drug responsiveness.…”

mentioning

confidence: 99%

“…Proteins that regulate GPCR signaling, such as GPCR kinases and ␤-arrestins, have been shown to define receptor responsiveness to drugs and endogenous neurotransmitters in vivo (3)(4)(5)(6)(7)(8)(9). Because ␤-arrestins can both desensitize and promote GPCR signaling, they are particularly well positioned to play a significant role in ligand-directed functional signaling (2).…”

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confidence: 99%

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Agonist-directed signaling of the serotonin 2A receptor depends on β-arrestin-2 interactions in vivo

Schmid

Raehal

Bohn

2008

Proc. Natl. Acad. Sci. U.S.A.

205

216

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Visual and auditory hallucinations accompany certain neuropsychiatric disorders, such as schizophrenia, and they also can be induced by the use or abuse of certain drugs. The heptahelical serotonin 2A receptors (5-HT2ARs) are molecular targets for druginduced hallucinations. However, the cellular mechanisms by which the 5-HT2AR mediates these effects are not well understood. Drugs acting at the 5-HT2AR can trigger diverse signaling pathways that may be directed by the chemical properties of the drug. ␤-arrestins are intracellular proteins that bind to heptahelical receptors and represent a point where such divergences in liganddirected functional signaling could occur. Here we compare the endogenous agonist, serotonin, to a synthetic 5-HT2AR hallucinogenic agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI), in mice lacking ␤-arrestin-2, as well as in cells lacking ␤-arrestins. In mice, we find that serotonin induces a head twitch response by a ␤-arrestin-2-dependent mechanism. However, DOI invokes the behavior independent of ␤-arrestin-2. The two structurally distinct agonists elicit different signal transduction and trafficking patterns upon activation of 5-HT2AR, which hinge on the presence of ␤-arrestins. Our study suggests that the 5-HT2AR-␤-arrestin interaction may be particularly important in receptor function in response to endogenous serotonin levels, which could have major implications in drug development for treating neuropsychiatric disorders such as depression and schizophrenia.5-HT2A receptor ͉ G protein-coupled receptor ͉ internalization ͉ MAP kinase ͉ schizophrenia

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Section: Discussionmentioning

confidence: 53%

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confidence: 99%

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confidence: 99%

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Agonist-directed signaling of the serotonin 2A receptor depends on β-arrestin-2 interactions in vivo

Schmid

Raehal

Bohn

2008

Proc. Natl. Acad. Sci. U.S.A.

205

216

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“…In fact, such functional selectivity has been shown recently for different GPCRs such as the ␤ 2 -adrenergic receptor, angiotensin II type 1 receptor (AT 1 ), CCR7, CXCR4, and the -opioid receptor (for review see ref. 27). Furthermore, one leading hypothesis to explain the unique clinical properties of atypical antipsychotics such as clozapine, postulates the importance of non-dopaminergic actions, particularly at serotonin receptors.…”

Section: Discussionmentioning

confidence: 99%

Antagonism of dopamine D2 receptor/β-arrestin 2 interaction is a common property of clinically effective antipsychotics

Masri

Salahpour

Didriksen

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

299

305

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Since the unexpected discovery of the antipsychotic activity of chlorpromazine, a variety of therapeutic agents have been developed for the treatment of schizophrenia. Despite differences in their activities at various neurotransmitter systems, all clinically effective antipsychotics share the ability to interact with D2 class dopamine receptors (D2R). D2R mediate their physiological effects via both G protein-dependent and independent (␤-arrestin 2-dependent) signaling, but the role of these D2R-mediated signaling events in the actions of antipsychotics remains unclear. We demonstrate here that while different classes of antipsychotics have complex pharmacological profiles at G protein-dependent D2R long isoform (D2 LR) signaling, they share the common property of antagonizing dopamine-mediated interaction of D2 LR with ␤-arrestin 2. Using two cellular assays based on a bioluminescence resonance energy transfer (BRET) approach, we demonstrate that a series of antipsychotics including haloperidol, clozapine, aripiprazole, chlorpromazine, quetiapine, olanzapine, risperidone, and ziprasidone all potently antagonize the ␤-arrestin 2 recruitment to D2 LR induced by quinpirole. However, these antipsychotics have various effects on D2 LR mediated Gi/o protein activation ranging from inverse to partial agonists and antagonists with highly variable efficacies and potencies at quinpirole-induced cAMP inhibition. These results suggest that the different classes of clinically effective antipsychotics share a common molecular mechanism involving inhibition of D2 LR/␤-arrestin 2 mediated signaling. Thus, selective targeting of D2LR/␤-arrestin 2 interaction and related signaling pathways may provide new opportunities for antipsychotic development.BRET ͉ schizophrenia ͉ signaling ͉ functional selectivity

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“…The concept of selective receptor modulators is probably most widely recognized in the nuclear receptor field where it has had an enormous impact on steroid receptor targeted therapeutics (Jordan, 2007). However, recent studies have demonstrated that the general concept of selective receptor modulators also applies to GPCRs (for recent reviews see (Galandrin et al, 2007;Kenakin, 2004;Neubig, 2007;Perez and Karnik, 2005;Urban et al, 2007;Violin and Lefkowitz, 2007)) and this evolution in our understanding again promises to have important consequences for drug development (Mailman, 2007). New terms have been coined to describe the idea that agonists can selectively activate different signaling pathways and responses via a single GPCR.…”

Section: Ligand Binding and Functional Selectivity In G Protein Couplmentioning

confidence: 99%

Selective agonism in somatostatin receptor signaling and regulation

Schönbrunn¹

2008

Molecular and Cellular Endocrinology

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SummaryThe five somatostatin receptor subtypes, named sst1 to sst5, activate both distinct and common signaling pathways and exhibit different patterns of receptor regulation. Until recently it was believed that once a particular somatostatin receptor was activated by an agonist, all the downstream signaling and regulatory effects characteristic of that receptor subtype in that cellular environment would be triggered. Thus, differences in the actions of somatostatin analogs between tissues were attributed to variability in the nature and concentration of the sst receptor subtypes and effectors expressed in different targets. However, agonists have recently been shown to exhibit functional selectivity at individual sst receptors such that they can elicit a subset of that receptor's potential effects, a property known as biased agonism. This review will summarize the evidence for functionally selective somatostatin receptor agonists and discuss the implications and promise of these new findings.

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β-Arrestin-biased ligands at seven-transmembrane receptors

Cited by 546 publications

References 43 publications

Agonist-directed signaling of the serotonin 2A receptor depends on β-arrestin-2 interactions in vivo

Agonist-directed signaling of the serotonin 2A receptor depends on β-arrestin-2 interactions in vivo

Antagonism of dopamine D2 receptor/β-arrestin 2 interaction is a common property of clinically effective antipsychotics

Selective agonism in somatostatin receptor signaling and regulation

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