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Monitoring GPCR-β-arrestin1/2 Interactions in Real Time Living Systems to Accelerate Drug Discovery
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The ADP ribosylation factor nucleotide exchange factor ARNO promotes beta-arrestin release necessary for luteinizing

S Mukherjee1, V V Gurevich, J C Jones

  • 1Department of Cell and Molecular Biology, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, IL 60611, USA.

Proceedings of the National Academy of Sciences of the United States of America
|May 17, 2000
PubMed

Insights

Receptor desensitization involves beta-arrestin binding to the luteinizing hormone/choriogonadotropin receptor (LH/CGR). Arf6 activation releases beta-arrestin, regulating LH/CGR signaling and desensitization.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Cell Signaling

Background:

  • G protein-coupled receptor (GPCR) desensitization is a key regulatory mechanism.
  • The luteinizing hormone/choriogonadotropin receptor (LH/CGR) in ovarian follicles undergoes desensitization in response to luteinizing hormone (LH).
  • Previous work implicated beta-arrestin binding to the LH/CGR's third intracellular loop in desensitization, dependent on GTP and G(s) protein uncoupling.

Purpose of the Study:

  • To investigate the role of ADP ribosylation factors (Arfs) in LH/CGR desensitization.
  • To elucidate the mechanism by which beta-arrestin is recruited and released during LH/CGR desensitization.
  • To identify the specific Arf proteins involved in regulating LH/CGR signaling.

Main Methods:

  • Utilized ADP ribosylation factor nucleotide-binding site opener to mimic LH/CGR desensitization.
  • Employed synthetic N-terminal Arf6 peptides to block desensitization.
  • Investigated the effect of Arf activation on beta-arrestin release from the membrane.

Main Results:

  • LH/CGR desensitization was mimicked by an Arf nucleotide exchange factor, suggesting Arf6 activation.
  • Synthetic Arf6 peptides blocked LH/CGR desensitization, while Arf1 peptides did not.
  • Arf activation promotes beta-arrestin release from the membrane, making it available for LH/CGR.

Conclusions:

  • LH/CGR desensitization involves a GTP-dependent step mediated by Arf6 activation.
  • LH/CGR signaling utilizes both heterotrimeric G(s) and small G protein Arf6.
  • Arf6 activation provides a feedback mechanism for LH/CGR self-regulation through beta-arrestin release.

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