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|Title:||Protease-activated receptor-2 in endosomes signals persistent pain of irritable bowel syndrome|
|Citation:||Proceedings of the National Academy of Sciences of the United States of America, 2018; 115(31):E7438-E7447|
|Publisher:||National Academy of Sciences|
|Nestor N. Jimenez-Vargas, Luke A. Pattison, Peishen Zhao, TinaMarie Lieu, Rocco Latorre, Dane D. Jensen, Joel Castro, Luigi Aurelio, Giang T. Le, Bernard Flynn, Carmen Klein Herenbrink, Holly R. Yeatman, Laura Edgington-Mitchell, Christopher J. H. Porter, Michelle L. Halls, Meritxell Canals, Nicholas A. Veldhuis, Daniel P. Poole, Peter McLean, Gareth A. Hicks, Nicole Scheff, Elyssa Chen, Aditi Bhattacharya, Brian L. Schmidt, Stuart M. Brierley, Stephen J. Vanner, and Nigel W. Bunnett|
|Abstract:||Once activated at the surface of cells, G protein-coupled receptors (GPCRs) redistribute to endosomes, where they can continue to signal. Whether GPCRs in endosomes generate signals that contribute to human disease is unknown. We evaluated endosomal signaling of protease-activated receptor-2 (PAR₂), which has been proposed to mediate pain in patients with irritable bowel syndrome (IBS). Trypsin, elastase, and cathepsin S, which are activated in the colonic mucosa of patients with IBS and in experimental animals with colitis, caused persistent PAR₂-dependent hyperexcitability of nociceptors, sensitization of colonic afferent neurons to mechanical stimuli, and somatic mechanical allodynia. Inhibitors of clathrin- and dynamin-dependent endocytosis and of mitogen-activated protein kinase kinase-1 prevented trypsin-induced hyperexcitability, sensitization, and allodynia. However, they did not affect elastase- or cathepsin S-induced hyperexcitability, sensitization, or allodynia. Trypsin stimulated endocytosis of PAR₂, which signaled from endosomes to activate extracellular signal-regulated kinase. Elastase and cathepsin S did not stimulate endocytosis of PAR₂, which signaled from the plasma membrane to activate adenylyl cyclase. Biopsies of colonic mucosa from IBS patients released proteases that induced persistent PAR₂-dependent hyperexcitability of nociceptors, and PAR₂ association with β-arrestins, which mediate endocytosis. Conjugation to cholestanol promoted delivery and retention of antagonists in endosomes containing PAR₂. A cholestanol-conjugated PAR₂ antagonist prevented persistent trypsin- and IBS protease-induced hyperexcitability of nociceptors. The results reveal that PAR₂ signaling from endosomes underlies the persistent hyperexcitability of nociceptors that mediates chronic pain of IBS. Endosomally targeted PAR₂ antagonists are potential therapies for IBS pain. GPCRs in endosomes transmit signals that contribute to human diseases.|
|Keywords:||Endosomes; receptors; pain; proteases|
|Description:||Published online July 16, 2018|
|Rights:||© 2018 Published under the PNAS license|
|Appears in Collections:||Molecular and Biomedical Science publications|
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