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Intestinal neuropod cell GUCY2C regulates visceral pain

Visceral pain (VP) is a global problem with complex etiologies and limited therapeutic options. Guanylyl cyclase C (GUCY2C), an intestinal receptor producing cyclic GMP(cGMP), which regulates luminal fluid secretion, has emerged as a therapeutic target for VP. Indeed, FDA-approved GUCY2C agonists am...

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Autores principales: Barton, Joshua R., Londregan, Annie K., Alexander, Tyler D., Entezari, Ariana A., Bar-Ad, Shely, Cheng, Lan, Lepore, Angelo C., Snook, Adam E., Covarrubias, Manuel, Waldman, Scott A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9927949/
https://www.ncbi.nlm.nih.gov/pubmed/36548082
http://dx.doi.org/10.1172/JCI165578
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author Barton, Joshua R.
Londregan, Annie K.
Alexander, Tyler D.
Entezari, Ariana A.
Bar-Ad, Shely
Cheng, Lan
Lepore, Angelo C.
Snook, Adam E.
Covarrubias, Manuel
Waldman, Scott A.
author_facet Barton, Joshua R.
Londregan, Annie K.
Alexander, Tyler D.
Entezari, Ariana A.
Bar-Ad, Shely
Cheng, Lan
Lepore, Angelo C.
Snook, Adam E.
Covarrubias, Manuel
Waldman, Scott A.
author_sort Barton, Joshua R.
collection PubMed
description Visceral pain (VP) is a global problem with complex etiologies and limited therapeutic options. Guanylyl cyclase C (GUCY2C), an intestinal receptor producing cyclic GMP(cGMP), which regulates luminal fluid secretion, has emerged as a therapeutic target for VP. Indeed, FDA-approved GUCY2C agonists ameliorate VP in patients with chronic constipation syndromes, although analgesic mechanisms remain obscure. Here, we revealed that intestinal GUCY2C was selectively enriched in neuropod cells, a type of enteroendocrine cell that synapses with submucosal neurons in mice and humans. GUCY2C(hi) neuropod cells associated with cocultured dorsal root ganglia neurons and induced hyperexcitability, reducing the rheobase and increasing the resulting number of evoked action potentials. Conversely, the GUCY2C agonist linaclotide eliminated neuronal hyperexcitability produced by GUCY2C-sufficient — but not GUCY2C-deficient — neuropod cells, an effect independent of bulk epithelial cells or extracellular cGMP. Genetic elimination of intestinal GUCY2C amplified nociceptive signaling in VP that was comparable with chemically induced VP but refractory to linaclotide. Importantly, eliminating GUCY2C selectively in neuropod cells also increased nociceptive signaling and VP that was refractory to linaclotide. In the context of loss of GUCY2C hormones in patients with VP, these observations suggest a specific role for neuropod GUCY2C signaling in the pathophysiology and treatment of these pain syndromes.
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spelling pubmed-99279492023-02-15 Intestinal neuropod cell GUCY2C regulates visceral pain Barton, Joshua R. Londregan, Annie K. Alexander, Tyler D. Entezari, Ariana A. Bar-Ad, Shely Cheng, Lan Lepore, Angelo C. Snook, Adam E. Covarrubias, Manuel Waldman, Scott A. J Clin Invest Research Article Visceral pain (VP) is a global problem with complex etiologies and limited therapeutic options. Guanylyl cyclase C (GUCY2C), an intestinal receptor producing cyclic GMP(cGMP), which regulates luminal fluid secretion, has emerged as a therapeutic target for VP. Indeed, FDA-approved GUCY2C agonists ameliorate VP in patients with chronic constipation syndromes, although analgesic mechanisms remain obscure. Here, we revealed that intestinal GUCY2C was selectively enriched in neuropod cells, a type of enteroendocrine cell that synapses with submucosal neurons in mice and humans. GUCY2C(hi) neuropod cells associated with cocultured dorsal root ganglia neurons and induced hyperexcitability, reducing the rheobase and increasing the resulting number of evoked action potentials. Conversely, the GUCY2C agonist linaclotide eliminated neuronal hyperexcitability produced by GUCY2C-sufficient — but not GUCY2C-deficient — neuropod cells, an effect independent of bulk epithelial cells or extracellular cGMP. Genetic elimination of intestinal GUCY2C amplified nociceptive signaling in VP that was comparable with chemically induced VP but refractory to linaclotide. Importantly, eliminating GUCY2C selectively in neuropod cells also increased nociceptive signaling and VP that was refractory to linaclotide. In the context of loss of GUCY2C hormones in patients with VP, these observations suggest a specific role for neuropod GUCY2C signaling in the pathophysiology and treatment of these pain syndromes. American Society for Clinical Investigation 2023-02-15 /pmc/articles/PMC9927949/ /pubmed/36548082 http://dx.doi.org/10.1172/JCI165578 Text en © 2023 Barton et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Barton, Joshua R.
Londregan, Annie K.
Alexander, Tyler D.
Entezari, Ariana A.
Bar-Ad, Shely
Cheng, Lan
Lepore, Angelo C.
Snook, Adam E.
Covarrubias, Manuel
Waldman, Scott A.
Intestinal neuropod cell GUCY2C regulates visceral pain
title Intestinal neuropod cell GUCY2C regulates visceral pain
title_full Intestinal neuropod cell GUCY2C regulates visceral pain
title_fullStr Intestinal neuropod cell GUCY2C regulates visceral pain
title_full_unstemmed Intestinal neuropod cell GUCY2C regulates visceral pain
title_short Intestinal neuropod cell GUCY2C regulates visceral pain
title_sort intestinal neuropod cell gucy2c regulates visceral pain
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9927949/
https://www.ncbi.nlm.nih.gov/pubmed/36548082
http://dx.doi.org/10.1172/JCI165578
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