G protein-coupled receptor desensitization as a measure of signaling: modeling of arrestin recruitment to activated CCK-B receptors.

Journal Article (Journal Article)

Gastrin is one of the principle hormonal mediators of gastric acid secretion, and its cognate receptor (CCK-B) is a member of the superfamily of GPCRs. Patients with hypergastrinemia may present with a variety of symptoms, including gastric ulcers or malignant tumors. Thus, the molecular mechanisms that terminate CCK-B receptor signaling, as well as an ability to measure gastrin bioactivity in a timely manner, have important clinical implications. In order to assess CCK-B receptor regulation, we have constructed a single cell biosensor containing the CCK-B receptor and an arrestin/GFP chimera. The gastrin biosensor responded to both immunologically detectable gastrin-17 and undetectable pentagastrin, and was able to determine the gastrin bioactivity of serum from a patient with clinical hypergastrinemia. We determined that the CCK-B receptor binds arrestin with a pharmacology mirroring CCK-B receptor signaling through inositol phosphate, and that the rate of arrestin dissociation from internalized receptor mirrors receptor recycling to the plasma membrane. Moreover, the CCK-B recycling rate is intermediate between that of Class A GPCRs such as the beta2-adrenergic receptor and Class B GPCRs such as the vasopressin type 2 receptor. Mathematical modeling of these results indicates that a common receptor conformation may underlie both CCK-B signaling and desensitization. In addition to its use in drug screening, this methodology should generalize to other receptors for use in diagnosis and monitoring of bioactive ligands involved in GPCR-based disease.

Full Text

Duke Authors

Cited Authors

  • Barak, LS; Oakley, RH; Shetzline, MA

Published Date

  • June 2003

Published In

Volume / Issue

  • 1 / 3

Start / End Page

  • 409 - 424

PubMed ID

  • 15090178

International Standard Serial Number (ISSN)

  • 1540-658X

Digital Object Identifier (DOI)

  • 10.1089/154065803322163722


  • eng

Conference Location

  • United States