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Profiling of G protein-coupled receptors in vagal afferents reveals novel gut-to-brain sensing mechanisms
Open accessAbstract
G protein-coupled receptors (GPCRs) act as transmembrane molecular sensors of neurotransmitters, hormones, nutrients, and metabolites. Because unmyelinated vagal afferents richly innervate the gastrointestinal mucosa, gut-derived molecules may directly modulate the activity of vagal afferents through GPCRs. However, the types of GPCRs expressed in vagal afferents are largely unknown. Here, we determined the expression profile of all GPCRs expressed in vagal afferents of the mouse, with a special emphasis on those innervating the gastrointestinal tract. Using a combination of high-throughput quantitative PCR, RNA sequencing, and in situ hybridization, we systematically quantified GPCRs expressed in vagal unmyelinated Nav1.8-expressing afferents. GPCRs for gut hormones that were the most enriched in Nav1.8-expressing vagal unmyelinated afferents included NTSR1, NPY2R, CCK1R, and to a lesser extent, GLP1R, but not GHSR and GIPR. Interestingly, both GLP1R and NPY2R were coexpressed with CCK1R. In contrast, NTSR1 was coexpressed with GPR65, a marker preferentially enriched in intestinal mucosal afferents. Only few microbiome-derived metabolite sensors such as GPR35 and, to a lesser extent, GPR119 and CaSR were identified in the Nav1.8-expressing vagal afferents. GPCRs involved in lipid sensing and inflammation (e.g. CB1R, CYSLTR2, PTGER4), and neurotransmitters signaling (CHRM4, DRD2, CRHR2) were also highly enriched in Nav1.8-expressing neurons. Finally, we identified 21 orphan GPCRs with unknown functions in vagal afferents. Overall, this study provides a comprehensive description of GPCR-dependent sensing mechanisms in vagal afferents, including novel coexpression patterns, and conceivably coaction of key receptors for gut-derived molecules involved in gut-brain communication.
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“evidence suggests that there are distinct populations and subpopulations of vagal afferents responding to specific stimuli, including stretch (Williams et al., 2016a) or gut hormones (Egerod et al., 2018).”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Egerod et al., 2018
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Dicks, L. M. T., Botha, A., & Pohl‐Albertyn, C. (2026) · Gut Microbes · doi:10.1080/19490976.2026.2740906
A light-responsive engineered probiotic system to alleviate anxiety via gut-brain axis
Chang, Y., Hang, Z., Zhang, Y., Zhu, Y., Li, X., 王学军, & Zhang, D. (2026) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2026.1864003
Metadata
- Authors
- Egerod, K. L., Petersen, N., Timshel, P. N., Rekling, J. C., Wang, Y., Liu, Q., Schwartz, T. W., & Gautron, L.
- Affiliations
- University of Copenhagen (DK)
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Egerod, Kristoffer L.
- Gautron, Laurent
- ORCID
- Venue
- Molecular Metabolism
- Publisher
- Elsevier BV
- Published
- 2018-06
- Volume
- 12
- Pages
- 62-75
- ISSN
- 2212-8778 (ISSN-L)
- PMC
- PMC6001940
- OpenAlex
- W2795588855
- Cited by
- 191
- References
- 85
- Citations by year
- 2026: 17 · 2025: 21 · 2024: 36 · 2023: 20 · 2022: 21 · 2021: 29 · 2020: 21 · 2019: 21 · 2018: 5
- FWCI
- 18.10
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Metabolism (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Danmarks Frie Forskningsfond (7016-00389A, NNF14OC0016798, NNF15CC0018346, NNF15OC0016798)
- Novo Nordisk Fonden (NNF10CC1016515)
- Topics
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- G protein-coupled receptors, vagal afferents, gut-brain signaling, gastrointestinal hormones, neurotensin receptor 1, NPY2R, GLP-1 receptor, GPR65, GPR35, GPR119, calcium-sensing receptor, gut microbiota metabolites, lipid sensing, inflammation, orphan G protein-coupled receptor, gastrointestinal mucosa, receptor co-expression
- MeSH terms
- Animals, Brain, Cells, Cultured, Gastrointestinal Hormones, Intestinal Mucosa, Male, Mice, Inbred C57BL, Neurons, Afferent, Vagus Nerve, Signal Transduction, Receptors, G-Protein-Coupled, Mice, NAV1.8 Voltage-Gated Sodium Channel
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