Complexes of Ghrelin GHS-R1a, GHS-R1b, and Dopamine D₁ Receptors Localized in the Ventral Tegmental Area as Main Mediators of the Dopaminergic Effects of Ghrelin

Authors

Gemma Navarro, University of Barcelona
William Rea, National Institutes of Health
César Quiroz, National Institutes of Health
Estefanía Moreno, University of Barcelona
Devan Gomez, Marquette University
Cody J. Wenthur, University of Wisconsin - Madison
Vicent Casadó, University of Barcelona
Lorenzo Leggio, National Institutes of Health
Matthew C. Hearing, Marquette UniversityFollow
Sergi Ferré, National Institutes of Health

Document Type

Article

Publication Date

2-9-2022

Publisher

Society for Neuroscience

Source Publication

Journal of Neuroscience

Source ISSN

0270-6474

Abstract

Ghrelin receptor, also known as growth hormone secretagogue receptor (GHS-R1a), is coexpressed with its truncated isoform GHS-R1b, which does not bind ghrelin or signal, but oligomerizes with GHS-R1a, exerting a complex modulatory role that depends on its relative expression. D₁ dopamine receptor (D1R) and D5R constitute the two D₁-like receptor subtypes. Previous studies showed that GHS-R1b also facilitates oligomerization of GHS-R1a with D1R, conferring GHS-R1a distinctive pharmacological properties. Those include a switch in the preferred coupling of GHS-R1a from Gq to Gs and the ability of D1R/D5R agonists and antagonists to counteract GHS-R1a signaling. Activation of ghrelin receptors localized in the ventral tegmental area (VTA) seems to play a significant role in the contribution of ghrelin to motivated behavior. In view of the evidence indicating that dopaminergic cells of the VTA express ghrelin receptors and D5R, but not D1R, we investigated the possible existence of functional GHS-R1a:GHS-R1b:D5R oligomeric complexes in the VTA. GHS-R1a:GHS-R1b:D5R oligomers were first demonstrated in mammalian transfected cells, and their pharmacological properties were found to be different from those of GHS-R1a:GHS-R1b:D1R oligomers, including weak Gs coupling and the ability of D1R/D5R antagonists, but not agonists, to counteract the effects of ghrelin. However, analyzing the effect of ghrelin in the rodent VTA on MAPK activation with ex vivo experiments, on somatodendritic dopamine release with in vivo microdialysis and on the activation of dopaminergic cells with patch-clamp electrophysiology, provided evidence for a predominant role of GHS-R1a:GHS-R1b:D1R oligomers in the rodent VTA as main mediators of the dopaminergic effects of ghrelin.

Comments

Published version. Journal of Neuroscience, Vol. 42, No. 6 (February 9, 2022): 940-953. DOI. © 2022 Society for Neuroscience. Used with permission.

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Recommended Citation

Navarro, Gemma; Rea, William; Quiroz, César; Moreno, Estefanía; Gomez, Devan; Wenthur, Cody J.; Casadó, Vicent; Leggio, Lorenzo; Hearing, Matthew C.; and Ferré, Sergi, "Complexes of Ghrelin GHS-R1a, GHS-R1b, and Dopamine D₁ Receptors Localized in the Ventral Tegmental Area as Main Mediators of the Dopaminergic Effects of Ghrelin" (2022). Biomedical Sciences Faculty Research and Publications. 212.
https://epublications.marquette.edu/biomedsci_fac/212