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The evolutionary divergence of receptor guanylyl cyclase C has implications for preclinical models for receptor-directed therapeutics
Mutations in receptor guanylyl cyclase C (GC-C) cause severe gastrointestinal disease, including meconium ileus, early onset acute diarrhea, and pediatric inflammatory bowel disease that continues into adulthood. Agonists of GC-C are US Food and Drug Administration-approved drugs for the treatment o...
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Published in: | The Journal of biological chemistry 2024-01, Vol.300 (1), p.105505-105505, Article 105505 |
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creator | Mishra, Vishwas Sharma, Kritica Bose, Avipsa Maisonneuve, Pierre Visweswariah, Sandhya S |
description | Mutations in receptor guanylyl cyclase C (GC-C) cause severe gastrointestinal disease, including meconium ileus, early onset acute diarrhea, and pediatric inflammatory bowel disease that continues into adulthood. Agonists of GC-C are US Food and Drug Administration-approved drugs for the treatment of constipation and irritable bowel syndrome. Therapeutic strategies targeting GC-C are tested in preclinical mouse models, assuming that murine GC-C mimics human GC-C in its biochemical properties and downstream signaling events. Here, we reveal important differences in ligand-binding affinity and GC activity between mouse GC-C and human GC-C. We generated a series of chimeric constructs of various domains of human and mouse GC-C to show that the extracellular domain of mouse GC-C contributed to log-orders lower affinity of mouse GC-C for ligands than human GC-C. Further, the Vmax of the murine GC domain was lower than that of human GC-C, and allosteric regulation of the receptor by ATP binding to the intracellular kinase-homology domain also differed. These altered properties are reflected in the high concentrations of ligands required to elicit signaling responses in the mouse gut in preclinical models and the specificity of a GC inhibitor towards human GC-C. Therefore, our studies identify considerations in using the murine model to test molecules for therapeutic purposes that work as either agonists or antagonists of GC-C, and vaccines for the bacterial heat-stable enterotoxin that causes watery diarrhea in humans. |
doi_str_mv | 10.1016/j.jbc.2023.105505 |
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Agonists of GC-C are US Food and Drug Administration-approved drugs for the treatment of constipation and irritable bowel syndrome. Therapeutic strategies targeting GC-C are tested in preclinical mouse models, assuming that murine GC-C mimics human GC-C in its biochemical properties and downstream signaling events. Here, we reveal important differences in ligand-binding affinity and GC activity between mouse GC-C and human GC-C. We generated a series of chimeric constructs of various domains of human and mouse GC-C to show that the extracellular domain of mouse GC-C contributed to log-orders lower affinity of mouse GC-C for ligands than human GC-C. Further, the Vmax of the murine GC domain was lower than that of human GC-C, and allosteric regulation of the receptor by ATP binding to the intracellular kinase-homology domain also differed. These altered properties are reflected in the high concentrations of ligands required to elicit signaling responses in the mouse gut in preclinical models and the specificity of a GC inhibitor towards human GC-C. Therefore, our studies identify considerations in using the murine model to test molecules for therapeutic purposes that work as either agonists or antagonists of GC-C, and vaccines for the bacterial heat-stable enterotoxin that causes watery diarrhea in humans.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1016/j.jbc.2023.105505</identifier><identifier>PMID: 38029963</identifier><language>eng</language><publisher>United States: American Society for Biochemistry and Molecular Biology</publisher><subject>Animals ; Biochemistry, Molecular Biology ; Chemical Sciences ; Child ; Diarrhea ; Enterotoxins ; Gastrointestinal Diseases - drug therapy ; Gastrointestinal Diseases - metabolism ; Gastrointestinal Diseases - pathology ; Genomics ; Guanylate Cyclase - metabolism ; Human health and pathology ; Humans ; Hépatology and Gastroenterology ; Life Sciences ; Ligands ; Medicinal Chemistry ; Mice ; Receptors, Enterotoxin - genetics ; Receptors, Guanylate Cyclase-Coupled - antagonists & inhibitors ; Receptors, Guanylate Cyclase-Coupled - genetics ; Receptors, Guanylate Cyclase-Coupled - metabolism</subject><ispartof>The Journal of biological chemistry, 2024-01, Vol.300 (1), p.105505-105505, Article 105505</ispartof><rights>Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c2455-aefbdd78446d127d465a72824c9328ee1961e657872b0c1bb0962e0a5c21373d3</cites><orcidid>0000-0002-7069-4613 ; 0000-0001-8292-5741</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,4024,27923,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38029963$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-04658947$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Mishra, Vishwas</creatorcontrib><creatorcontrib>Sharma, Kritica</creatorcontrib><creatorcontrib>Bose, Avipsa</creatorcontrib><creatorcontrib>Maisonneuve, Pierre</creatorcontrib><creatorcontrib>Visweswariah, Sandhya S</creatorcontrib><title>The evolutionary divergence of receptor guanylyl cyclase C has implications for preclinical models for receptor-directed therapeutics</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Mutations in receptor guanylyl cyclase C (GC-C) cause severe gastrointestinal disease, including meconium ileus, early onset acute diarrhea, and pediatric inflammatory bowel disease that continues into adulthood. Agonists of GC-C are US Food and Drug Administration-approved drugs for the treatment of constipation and irritable bowel syndrome. Therapeutic strategies targeting GC-C are tested in preclinical mouse models, assuming that murine GC-C mimics human GC-C in its biochemical properties and downstream signaling events. Here, we reveal important differences in ligand-binding affinity and GC activity between mouse GC-C and human GC-C. We generated a series of chimeric constructs of various domains of human and mouse GC-C to show that the extracellular domain of mouse GC-C contributed to log-orders lower affinity of mouse GC-C for ligands than human GC-C. Further, the Vmax of the murine GC domain was lower than that of human GC-C, and allosteric regulation of the receptor by ATP binding to the intracellular kinase-homology domain also differed. These altered properties are reflected in the high concentrations of ligands required to elicit signaling responses in the mouse gut in preclinical models and the specificity of a GC inhibitor towards human GC-C. Therefore, our studies identify considerations in using the murine model to test molecules for therapeutic purposes that work as either agonists or antagonists of GC-C, and vaccines for the bacterial heat-stable enterotoxin that causes watery diarrhea in humans.</description><subject>Animals</subject><subject>Biochemistry, Molecular Biology</subject><subject>Chemical Sciences</subject><subject>Child</subject><subject>Diarrhea</subject><subject>Enterotoxins</subject><subject>Gastrointestinal Diseases - drug therapy</subject><subject>Gastrointestinal Diseases - metabolism</subject><subject>Gastrointestinal Diseases - pathology</subject><subject>Genomics</subject><subject>Guanylate Cyclase - metabolism</subject><subject>Human health and pathology</subject><subject>Humans</subject><subject>Hépatology and Gastroenterology</subject><subject>Life Sciences</subject><subject>Ligands</subject><subject>Medicinal Chemistry</subject><subject>Mice</subject><subject>Receptors, Enterotoxin - genetics</subject><subject>Receptors, Guanylate Cyclase-Coupled - antagonists & inhibitors</subject><subject>Receptors, Guanylate Cyclase-Coupled - genetics</subject><subject>Receptors, Guanylate Cyclase-Coupled - metabolism</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><recordid>eNo9kc1u3CAUhVHVqpkmfYBuKpbNwlN-jIFlNGqTSiN1k0rZIQzXGUb4p2CPNA_Q9y4jJ2EDHJ1zruBD6AslW0po8_24PbZuywjj5S4EEe_QhhLFKy7o03u0IYTRSjOhrtCnnI-krFrTj-iKK8K0bvgG_Xs8AIbTGJc5jINNZ-zDCdIzDA7w2OEEDqZ5TPh5scM5niN2ZxdtBrzDB5tx6KcYnL2EM-6KbyqJGIaiRdyPHuIqv_ZUPpTjDB7PB0h2gjLX5Rv0obMxw-eX_Rr9-fnjcfdQ7X_f_9rd7SvHaiEqC13rvVR13XjKpK8bYSVTrHaaMwVAdUOhEVJJ1hJH25bohgGxwjHKJff8Gt2uvQcbzZRCXx5sRhvMw93eXDRSKpWu5YkW77fVO6Xx7wJ5Nn3IDmK0A4xLNkxpIcs3UlmsdLW6NOacoHvrpsRcSJmjKaTMhZRZSZXM15f6pe3BvyVe0fD_Y9-RWg</recordid><startdate>202401</startdate><enddate>202401</enddate><creator>Mishra, Vishwas</creator><creator>Sharma, Kritica</creator><creator>Bose, Avipsa</creator><creator>Maisonneuve, Pierre</creator><creator>Visweswariah, Sandhya S</creator><general>American Society for Biochemistry and Molecular Biology</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>1XC</scope><scope>VOOES</scope><orcidid>https://orcid.org/0000-0002-7069-4613</orcidid><orcidid>https://orcid.org/0000-0001-8292-5741</orcidid></search><sort><creationdate>202401</creationdate><title>The evolutionary divergence of receptor guanylyl cyclase C has implications for preclinical models for receptor-directed therapeutics</title><author>Mishra, Vishwas ; 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Agonists of GC-C are US Food and Drug Administration-approved drugs for the treatment of constipation and irritable bowel syndrome. Therapeutic strategies targeting GC-C are tested in preclinical mouse models, assuming that murine GC-C mimics human GC-C in its biochemical properties and downstream signaling events. Here, we reveal important differences in ligand-binding affinity and GC activity between mouse GC-C and human GC-C. We generated a series of chimeric constructs of various domains of human and mouse GC-C to show that the extracellular domain of mouse GC-C contributed to log-orders lower affinity of mouse GC-C for ligands than human GC-C. Further, the Vmax of the murine GC domain was lower than that of human GC-C, and allosteric regulation of the receptor by ATP binding to the intracellular kinase-homology domain also differed. These altered properties are reflected in the high concentrations of ligands required to elicit signaling responses in the mouse gut in preclinical models and the specificity of a GC inhibitor towards human GC-C. Therefore, our studies identify considerations in using the murine model to test molecules for therapeutic purposes that work as either agonists or antagonists of GC-C, and vaccines for the bacterial heat-stable enterotoxin that causes watery diarrhea in humans.</abstract><cop>United States</cop><pub>American Society for Biochemistry and Molecular Biology</pub><pmid>38029963</pmid><doi>10.1016/j.jbc.2023.105505</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0002-7069-4613</orcidid><orcidid>https://orcid.org/0000-0001-8292-5741</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Animals Biochemistry, Molecular Biology Chemical Sciences Child Diarrhea Enterotoxins Gastrointestinal Diseases - drug therapy Gastrointestinal Diseases - metabolism Gastrointestinal Diseases - pathology Genomics Guanylate Cyclase - metabolism Human health and pathology Humans Hépatology and Gastroenterology Life Sciences Ligands Medicinal Chemistry Mice Receptors, Enterotoxin - genetics Receptors, Guanylate Cyclase-Coupled - antagonists & inhibitors Receptors, Guanylate Cyclase-Coupled - genetics Receptors, Guanylate Cyclase-Coupled - metabolism |
title | The evolutionary divergence of receptor guanylyl cyclase C has implications for preclinical models for receptor-directed therapeutics |
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