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Beyond desensitization: physiological relevance of arrestin-dependent signaling.

Publication ,  Journal Article
Luttrell, LM; Gesty-Palmer, D
Published in: Pharmacol Rev
June 2010

Heptahelical G protein-coupled receptors are the most diverse and therapeutically important family of receptors in the human genome. Ligand binding activates heterotrimeric G proteins that transmit intracellular signals by regulating effector enzymes or ion channels. G protein signaling is terminated, in large part, by arrestin binding, which uncouples the receptor and G protein and targets the receptor for internalization. It is clear, however, that heptahelical receptor signaling does not end with desensitization. Arrestins bind a host of catalytically active proteins and serve as ligand-regulated scaffolds that recruit protein and lipid kinase, phosphatase, phosphodiesterase, and ubiquitin ligase activity into the receptor-arrestin complex. Although many of these arrestin-bound effectors serve to modulate G protein signaling, degrading second messengers and regulating endocytosis and trafficking, other signals seem to extend beyond the receptor-arrestin complex to regulate such processes as protein translation and gene transcription. Although these findings have led to a re-envisioning of heptahelical receptor signaling, little is known about the physiological roles of arrestin-dependent signaling. In vivo, the duality of arrestin function makes it difficult to dissociate the consequences of arrestin-dependent desensitization from those that might be ascribed to arrestin-mediated signaling. Nonetheless, recent evidence generated using arrestin knockouts, G protein-uncoupled receptor mutants, and arrestin pathway-selective "biased agonists" is beginning to reveal that arrestin signaling plays important roles in the retina, central nervous system, cardiovascular system, bone remodeling, immune system, and cancer. Understanding the signaling roles of arrestins may foster the development of pathway-selective drugs that exploit these pathways for therapeutic benefit.

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Published In

Pharmacol Rev

DOI

EISSN

1521-0081

Publication Date

June 2010

Volume

62

Issue

2

Start / End Page

305 / 330

Location

United States

Related Subject Headings

  • Signal Transduction
  • Receptors, G-Protein-Coupled
  • Pharmacology & Pharmacy
  • Humans
  • Heterotrimeric GTP-Binding Proteins
  • GTP-Binding Protein Regulators
  • Endocytosis
  • Arrestin
  • 3214 Pharmacology and pharmaceutical sciences
  • 1115 Pharmacology and Pharmaceutical Sciences
 

Citation

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Luttrell, L. M., & Gesty-Palmer, D. (2010). Beyond desensitization: physiological relevance of arrestin-dependent signaling. Pharmacol Rev, 62(2), 305–330. https://doi.org/10.1124/pr.109.002436
Luttrell, Louis M., and Diane Gesty-Palmer. “Beyond desensitization: physiological relevance of arrestin-dependent signaling.Pharmacol Rev 62, no. 2 (June 2010): 305–30. https://doi.org/10.1124/pr.109.002436.
Luttrell LM, Gesty-Palmer D. Beyond desensitization: physiological relevance of arrestin-dependent signaling. Pharmacol Rev. 2010 Jun;62(2):305–30.
Luttrell, Louis M., and Diane Gesty-Palmer. “Beyond desensitization: physiological relevance of arrestin-dependent signaling.Pharmacol Rev, vol. 62, no. 2, June 2010, pp. 305–30. Pubmed, doi:10.1124/pr.109.002436.
Luttrell LM, Gesty-Palmer D. Beyond desensitization: physiological relevance of arrestin-dependent signaling. Pharmacol Rev. 2010 Jun;62(2):305–330.
Journal cover image

Published In

Pharmacol Rev

DOI

EISSN

1521-0081

Publication Date

June 2010

Volume

62

Issue

2

Start / End Page

305 / 330

Location

United States

Related Subject Headings

  • Signal Transduction
  • Receptors, G-Protein-Coupled
  • Pharmacology & Pharmacy
  • Humans
  • Heterotrimeric GTP-Binding Proteins
  • GTP-Binding Protein Regulators
  • Endocytosis
  • Arrestin
  • 3214 Pharmacology and pharmaceutical sciences
  • 1115 Pharmacology and Pharmaceutical Sciences