Journal article
Protease-activated receptor-2 in endosomes signals persistent pain of irritable bowel syndrome
NN Jimenez-Vargas, LA Pattison, P Zhao, TM Lieu, R Latorre, DD Jensen, J Castro, L Aurelio, GT Le, B Flynn, CK Herenbrink, HR Yeatman, L Edgington-Mitchell, CJH Porter, ML Halls, M Canals, NA Veldhuis, DP Poole, P McLean, GA Hicks Show all
Proceedings of the National Academy of Sciences of the United States of America | NATL ACAD SCIENCES | Published : 2018
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. Inh..
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Awarded by National Institutes of Health
Funding Acknowledgements
This work was supported by NIH Grant NS102722 (to N.W.B.); National Health Medical and Research Council (NHMRC) Grants 63303, 1049682, and 1031886 (to N.W.B.); Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology (N.W.B.); Takeda Pharmaceuticals, Inc. (N.W.B.); NIH Grant DE026806 (to N.W.B. and B.L.S.); NIH Grant DE025393 (to B.L.S.); and the Canadian Institute of Health (S.J.V.). M.L.H. is an NHMRC RD Wright Career Development Fellow (1061687); S.M.B. is an NHMRC RD Wright Biomedical Research Fellow (1126378); and M.C. is a Monash Fellow.