Mishra, V and Sharma, K and Bose, A and Maisonneuve, P and Visweswariah, SS (2024) The evolutionary divergence of receptor guanylyl cyclase C has implications for preclinical models for receptor-directed therapeutics. In: Journal of Biological Chemistry, 300 (1).
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Abstract
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. © 2023 The Authors
| Item Type: | Journal Article |
|---|---|
| Publication: | Journal of Biological Chemistry |
| Publisher: | American Society for Biochemistry and Molecular Biology Inc. |
| Additional Information: | The copyright for this article belongs to author. |
| Keywords: | Binding energy; Enzymes, Bacterial toxin; CGMP; Guanylin; Guanylyl cyclase; Kinase; Linaclotide; Plecanatide; Receptor guanylyl cyclase C; Uroguanylin, Ligands, enterotoxin; guanylate cyclase; receptor guanylyl cyclase C; unclassified drug, allosterism; animal experiment; animal tissue; Article; binding affinity; controlled study; enzyme activity; enzyme inhibition; enzyme specificity; evolutionary adaptation; HEK293-EBNA cell line; human; human cell; human tissue; in vitro study; maximum reaction velocity; mouse; nonhuman; protein domain; protein expression; quantitative analysis; real time polymerase chain reaction; receptor binding assay; signal transduction; Western blotting |
| Department/Centre: | Others |
| Date Deposited: | 01 Mar 2024 09:17 |
| Last Modified: | 01 Mar 2024 09:17 |
| URI: | https://eprints.iisc.ac.in/id/eprint/83976 |
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