Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • Immune Environment in Glioblastoma (Feb 2023)
    • Korsmeyer Award 25th Anniversary Collection (Jan 2023)
    • Aging (Jul 2022)
    • Next-Generation Sequencing in Medicine (Jun 2022)
    • New Therapeutic Targets in Cardiovascular Diseases (Mar 2022)
    • Immunometabolism (Jan 2022)
    • Circadian Rhythm (Oct 2021)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Commentaries
    • Research letters
    • Letters to the editor
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • In-Press Preview
  • Commentaries
  • Research letters
  • Letters to the editor
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
Ghrelin receptor mutations — too little height and too much hunger
Birgitte Holst, Thue W. Schwartz
Birgitte Holst, Thue W. Schwartz
Published March 1, 2006
Citation Information: J Clin Invest. 2006;116(3):637-641. https://doi.org/10.1172/JCI27999.
View: Text | PDF
Commentary

Ghrelin receptor mutations — too little height and too much hunger

  • Text
  • PDF
Abstract

The ghrelin receptor is known from in vitro studies to signal in the absence of the hormone ghrelin at almost 50% of its maximal capacity. But, as for many other 7-transmembrane receptors, the in vivo importance of this ligand-independent signaling has remained unclear. In this issue of the JCI, Pantel et al. find that a natural mutation in the ghrelin receptor, Ala204Glu, which is associated with a selective loss of constitutive activity without affecting ghrelin affinity, potency, or efficacy, segregates in 2 families with the development of short stature (see the related article beginning on page 760). By combination of the observations from this study with those related to the phenotype of subjects carrying another natural ghrelin receptor mutation, Phe279Leu, having identical molecular-pharmacological properties, it is proposed that selective lack of ghrelin receptor constitutive signaling leads to a syndrome characterized not only by short stature, but also by obesity that apparently develops during puberty.

Authors

Birgitte Holst, Thue W. Schwartz

×

Figure 1

Constitutive and hormone-mediated signaling of the ghrelin receptor in relation to the dynamic pattern of ghrelin secretion.

Options: View larger image (or click on image) Download as PowerPoint
Constitutive and hormone-mediated signaling of the ghrelin receptor in r...
(A) Variations in plasma ghrelin concentration (conc.) depicted as a dynamic range in relation to a meal. Note the pre-meal surge in ghrelin secretion followed by inhibition related to the presence of food in the upper gastrointestinal tract. Illustration based on work of Cummings and coworkers (12, 13). (B) Illustration of the almost 50% constitutive, ligand-independent signaling of the ghrelin receptor as measured, for example, in inositol phosphate accumulation assays and the agonist response mediated by the ghrelin hormone (4). To the upper left is indicated that the high constitutive ghrelin receptor signaling is expected to be dominant in the inter-meal period, while the ghrelin-mediated signaling is most important in the fasting state and pre-meal situation (10). (C) Diagram of the theoretical effect of an inverse agonist, which inhibits constitutive signaling; the effect of a pure antagonist, which blocks the agonist-mediated signaling without affecting the constitutive signaling; and the effect of a combined antagonist and inverse agonist (dotted curve in blue), which blocks both the agonist-induced signaling and the constitutive signaling. It should be noted that for 7TM receptors in general, antagonists generally also act as inverse agonists, a phenomenon whose salience depends on the receptor displaying a reasonable degree of constitutive signaling. However, compounds have been described — for example, in the ghrelin receptor system — that are significantly more potent as inverse agonists than as antagonists (4).

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts