A potential novel strategy to separate therapeutic- and side-effects that are mediated via the same receptor: beta-arrestin2/G-protein coupling antagonists

Bruns, Ingmar; Chhum, S.; Dinh, Andy; Dunn, Nick; Ly, Yin; Mitman, C. L.; Rickards, H. D.; Sol, C.; Wan, E. W.; Raffa, Robert B.

doi:10.1111/j.1365-2710.2006.00714.x

Cited by 16 publications

(7 citation statements)

References 56 publications

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“…The mechanisms that determine how one OR-mediated physiological response can be enhanced while another is suppressed due to the ablation of ␤arr2 is not known; however, these observations speak to the diverse roles that ␤-arrestins may play in receptor signaling and regulation (Shenoy and Lefkowitz, . If ␤arr2-opioid receptor interaction is required for opioid-induced constipation and respiratory suppression, then compounds that can activate the OR and not recruit the ␤-arrestins may be promising opioid analgesics with much fewer side effects (Bruns et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

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An Opioid Agonist that Does Not Induce μ-Opioid Receptor—Arrestin Interactions or Receptor Internalization

Groer¹,

Tidgewell²,

Moyer³

et al. 2007

Molecular Pharmacology

211

220

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G protein-coupled receptor desensitization and trafficking are important regulators of opioid receptor signaling that can dictate overall drug responsiveness in vivo. Furthermore, different -opioid receptor (OR) ligands can lead to varying degrees of receptor regulation, presumably because of distinct structural conformations conferred by agonist binding. For example, morphine binding produces a OR with low affinity for ␤-arrestin proteins and limited receptor internalization, whereas enkephalin analogs promote robust trafficking of both ␤-arrestins and the receptors. Here, we evaluate OR trafficking in response to activation by a novel -selective agonist derived from the naturally occurring plant product, salvinorin A. It is interesting that this compound, termed herkinorin, does not promote the recruitment of ␤-arrestin-2 to the OR and does not lead to receptor internalization. Moreover, whereas G protein-coupled receptor kinase overexpression can promote morphine-induced ␤-arrestin interactions and OR internalization, such manipulations do not promote herkinorin-induced trafficking. Studies in mice have shown that ␤-arrestin-2 plays an important role in the development of morphine-induced tolerance, constipation, and respiratory depression. Therefore, drugs that can activate the receptor without recruiting the arrestins may be a promising step in the development of opiate analgesics that distinguish between agonist activity and receptor regulation and may ultimately lead to therapeutics designed to provide pain relief without the adverse side effects normally associated with the opiate narcotics.

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Section: Discussionmentioning

confidence: 99%

“…It is somewhat of a surprise that these animals are not as susceptible to the morphine-induced side effects, including constipation and respiratory suppression . Therefore, the OR-␤arr2 interactions may represent a point at which agonist-directed signaling events diverge Bruns et al, 2006).…”

mentioning

confidence: 99%

An Opioid Agonist that Does Not Induce μ-Opioid Receptor—Arrestin Interactions or Receptor Internalization

Groer¹,

Tidgewell²,

Moyer³

et al. 2007

Molecular Pharmacology

211

220

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“…Arrestins consist of a family of four proteins, including the ubiquitously expressed b-arrestin 1 and b-arrestin 2 (also known as arrestin 2 and arrestin 3), in addition to two visual arrestins (arrestin 1 and arrestin 4) that are expressed exclusively in the retinae of mammals (Bruns et al, 2006). b-Arrestin 1 and b-arrestin 2, the classical regulators of G-protein-coupled receptors (GPCRs), not only negatively regulate GPCR-mediated signaling, but also serve as scaffolds and adapters in numerous crucial signal transduction pathways such as Wnt, Smo,p53, and MAPK cascades (Fraser, 2008;Morishita et al, 2007;Ruiz-Gó mez et al, 2007;Wang et al, 2002;Wang and Malbon, 2003).…”

Section: Introductionmentioning

confidence: 99%

Disruption of β-arrestins blocks glucocorticoid receptor and severely retards lung and liver development in mice

Zhang

Teng

Shi

et al. 2011

Mechanisms of Development

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In this study, the role of β-arrestin 1 and β-arrestin 2 in fetal lung and liver development was examined using Arrb1(-/-)Arrb2(-/-) mouse embryos. β-Arrestin 1/2 dual-null mice died shortly after birth and morphological examination revealed an obvious pulmonary hypoplasia and severe hepatic impairment. Western blot analysis demonstrated that GR protein levels in Arrb1(-/-)Arrb2(-/-) lung and liver tissues were significantly decreased compared to wild type embryos. Expression of GR proteins was confirmed in the nuclei of type II pneumocytes of 18.5 day embryos (E18.5) by immunofluorescence. The production of hepatic glucose and mRNA level of gluconeogenic enzymes were dramatically reduced in E18.5 Arrb1(-/-)Arrb2(-/-) liver. These results suggest that GR is an important downstream effector of the β-arrestin signaling pathway involved in regulation of lung and liver development. However, no obvious changes in GR expression following in vitro modulation of β-arrestin 1/2 indicated the existence of an indirect regulatory relationship between GR and the β-arrestin signaling pathway.

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“…Up to 2% of the human genome encodes GPCRs [1] . GPCRs are virtually expressed everywhere throughout the body, including the central nervous system, cardiovascular system, gastrointestinal tract, skeletomuscular system, urogenital system, reproductive system, and almost all other organs controlled by the autonomic nervous system [2] . GPCRs are activated by a diverse range of ligands, and play critical roles in physiology.…”

Section: Introductionmentioning

confidence: 99%

GPCR-CARMA3-NF-kappaB signaling axis: A novel drug target for cancer therapy

Sun

2010

Clin. Oncol. Cancer Res.

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A potential novel strategy to separate therapeutic- and side-effects that are mediated via the same receptor: beta-arrestin2/G-protein coupling antagonists

Cited by 16 publications

References 56 publications

An Opioid Agonist that Does Not Induce μ-Opioid Receptor—Arrestin Interactions or Receptor Internalization

An Opioid Agonist that Does Not Induce μ-Opioid Receptor—Arrestin Interactions or Receptor Internalization

Disruption of β-arrestins blocks glucocorticoid receptor and severely retards lung and liver development in mice

GPCR-CARMA3-NF-kappaB signaling axis: A novel drug target for cancer therapy

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