Dissertation
Mechanisms of MRAP2-mediated regulation of G protein-coupled receptors involved in the central control of energy homeostasis
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Autumn 2021
DOI: 10.17077/etd.006243
Abstract
The melanocortin receptor accessory protein-2 (MRAP2) is a single transmembrane accessory protein that complexes with G-protein coupled receptors (GPCRs) which controls major physiological signaling such as hunger and satiety feeling and energy homeostasis. While MRAP2 was initially discovered as a partner of the melanocortin-4 receptor, it was quickly discovered that the interactome of MRAP2 was broader.This thesis work reveals the effect of MRAP2 on the prokineticin receptor-1 (PKR1), Orexin-1 receptor (OX1R), and ghrelin receptor (GHSR1a). Herein, we are showing that MRAP2 inhibits trafficking and signaling of OX1R and PKR1. We also identify specific region of MRAP2 dedicated to the regulation of either OX1R or PKR1.
GHSR1a is activated by ghrelin, also known as the “hunger hormone”, which increases appetite. In rodents, deletion of GHSR1a has been shown to prevent diet induced obesity, improve insulin sensitivity as well as poor survival when exposed to calorie-restricted diet. The ghrelin system has been pharmaceutically exploited prematurely leading to poor clinical outcome. This work reveals the importance of MRAP2 in the ghrelin system. Throughout this study we demonstrate that MRAP2 potentiates ghrelin-stimulated Gαq signaling of GHSR1a by inhibiting its constitutive activity; also, we show that MRAP2 inhibits ghrelin-stimulated β-arrestin recruitment to GHSR1a by preventing the phosphorylation of the receptor through the inhibition of kinases recruitment to the receptor.
The present work identifies MRAP2 as a major GPCR regulator, which not only increase our understanding of the dynamic between MRAP2 and its target, but also identifies potential new targets for pharmaceutical solutions against obesity and associated diseases.
Details
- Title: Subtitle
- Mechanisms of MRAP2-mediated regulation of G protein-coupled receptors involved in the central control of energy homeostasis
- Creators
- Alix Arthur Jean Rouault
- Contributors
- Julien A Sebag (Advisor)Robert Piper (Committee Member)Michael G Anderson (Committee Member)Ling Yang (Committee Member)Matthew J Potthoff (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Molecular Physiology and Biophysics
- Date degree season
- Autumn 2021
- DOI
- 10.17077/etd.006243
- Publisher
- University of Iowa
- Number of pages
- xvi, 119 pages
- Copyright
- Copyright 2021 Alix A. J. Rouault
- Language
- English
- Description illustrations
- illustrations (chiefly color)
- Description bibliographic
- Includes bibliographical references (pages 69-78)
- Public Abstract (ETD)
Obesity and diabetes increase the risk of many diseases, including, cancers and cardiovascular diseases. Current treatments for both diabetes and obesity are insufficient. We have discovered a protein, MRAP2, that is important for feeling hunger, understanding how it works may allow for discovery of medicine to help people lose weight and be healthier. We investigated the role of several receptors with an emphasis on the ghrelin receptor. We showed that hunger sensing mediated by the hunger hormone, ghrelin, requires the accessory protein MRAP2. This thesis aimed to understand the role and mechanism through which MRAP2 modifies the response to ghrelin to regulate appetite. Improving our knowledge on how the brain senses hunger and regulates appetite is essential for the development of new strategies to treat obesity.
- Academic Unit
- Molecular Physiology and Biophysics
- Record Identifier
- 9984210748802771
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