Intestinal neuropod cell GUCY2C regulates visceral pain

• Published in: The Journal of clinical investigation 2023-02, Vol.133 (4), p.1-15
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Agonists; Analgesics; Animals; Biomedical research; Care and treatment; Cellular signal transduction; Constipation; Cyclic GMP; Cyclic GMP - metabolism; Cyclic guanylic acid; Development and progression; Dorsal root ganglia; Drug approval; Electrolytes; Enteroendocrine Cells - metabolism; Enteroendocrine Cells - physiology; Epithelial cells; Executives; Gastroenterology; Genes; Guanylate cyclase; Health aspects; Hormones; Humans; Intestine; Intestine, Small; Intestines - metabolism; Intestines - physiology; Irritable bowel syndrome; Kinases; Linaclotide; Mice; Morphology; Nervous system; Nervous system, Autonomic; Neurons; Neuroscience; Officials and employees; Pain; Pain perception; Pathophysiology; Physiological aspects; Proteins; Receptors, Enterotoxin - metabolism; Receptors, Guanylate Cyclase-Coupled - metabolism; Scientific equipment and supplies industry; Signal Transduction - physiology; Small intestine; Synapses; Therapeutic targets; Visceral Pain - genetics; Visceral Pain - metabolism
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI165578

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.