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Intestinal neuropod cell GUCY2C regulates visceral pain.

ABSTRACT: 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. GUCY2Chi 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.

SUBMITTER: Barton JR

PROVIDER: S-EPMC9927949 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Intestinal neuropod cell GUCY2C regulates visceral pain.

Barton Joshua R JR Londregan Annie K AK Alexander Tyler D TD Entezari Ariana A AA Bar-Ad Shely S Cheng Lan L Lepore Angelo C AC Snook Adam E AE Covarrubias Manuel M Waldman Scott A SA

The Journal of clinical investigation 20230215 4

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 o ...[more]

PMID: 36548082

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Project description:Background & aimsGUCY2C is the intestinal receptor for the paracrine hormones guanylin and uroguanylin that converts guanosine-5'-triphosphate to cyclic guanosine monophosphate (cGMP). It functions as a tumor suppressor; its loss disrupts intestinal homeostasis and promotes tumorigenesis. We investigated the effects of GUCY2C loss on intestinal cell proliferation, metabolism, signaling, and tumorigenesis in mice.MethodsIntestinal cell proliferation and metabolism were examined in Gucy2c(-/-) and colon cancer cells by microscopy, immunoblot, and functional analyses. Microarray analyses compared gene expression profiles of intestine cell from Gucy2c(-/-) and wild-type mice. v akt murine thymoma viral oncogene homolog (AKT) regulation and signaling were examined, and the role of AKT in GUCY2C-dependent tumorigenesis was defined in Gucy2c(-/-)Akt1(-/-) mice.ResultsThe size and number of intestinal crypts increased in Gucy2c(-/-) mice; the associated epithelial cells showed accelerated proliferation, increased glycolysis, and reduced oxidative phosphorylation, which was reversed by oral administration of cGMP. Conversely, activating guanylyl cyclase C in human colon cancer cells delayed cell-cycle progression, decreased DNA synthesis and colony formation, reduced glycolysis, and increased mitochondrial adenosine triphosphate production. AKT signaling pathways were activated in intestines of Gucy2c(-/-) mice, associated with increased AKT phosphorylation. Disruption of AKT activity, pharmacologically or genetically, reduced DNA synthesis, proliferation, and glycolysis, and increased mitochondrial biogenesis. Intestinal tumorigenesis increased after administration of azoxymethane to Gucy2c(-/-) mice, compared with wild-type mice, but was eliminated in Gucy2c(-/-)Akt1(-/-) mice.ConclusionsGUCY2C is a tumor suppressor that controls proliferation and metabolism of intestinal epithelial cells by inactivating AKT signaling. This receptor and its ligands, which are paracrine hormones, might be novel candidates for anticolorectal cancer therapy.

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Intestinal neuropod cell GUCY2C regulates visceral pain.

Publications

Intestinal neuropod cell GUCY2C regulates visceral pain.

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