دورية أكاديمية
Endosomal signaling of the receptor for calcitonin gene-related peptide mediates pain transmission
| العنوان: | Endosomal signaling of the receptor for calcitonin gene-related peptide mediates pain transmission |
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| المؤلفون: | Yarwood, R.E., Imlach, W.L., Lieu, T., Veldhuis, N.A., Jensen, D.D., Herenbrink, C.K., Aurelio, L., Cai, Zhijian, Christie, M.J., Poole, D.P., Porter, C.J.H., McLean, P., Hicks, G.A., Geppetti, P., Halls, M.L., Canals, M., Bunnett, N.W. |
| بيانات النشر: | National Academy of Sciences |
| سنة النشر: | 2017 |
| المجموعة: | University of Nottingham: Repository@Nottingham |
| مصطلحات موضوعية: | Endocytosis, G protein-coupled receptors, Neuropeptides, Nociception, Pain, calcitonin gene related peptide, calcitonin gene related peptide receptor, cholestanol, clathrin, dynamin, early endosome antigen 1, mitogen activated protein kinase, protein kina |
| الوصف: | G protein-coupled receptors (GPCRs) are considered to function primarily at the plasma membrane, where they interact with extracellular ligands and couple to G proteins that transmit intracellular signals. Consequently, therapeutic drugs are designed to target GPCRs at the plasma membrane. Activated GPCRs undergo clathrin-dependent endocytosis. Whether GPCRs in endosomes control pathophysiological processes in vivo and are therapeutic targets remains uncertain. We investigated the contribution of endosomal signaling of the calcitonin receptor-like receptor (CLR) to pain transmission. Calcitonin gene-related peptide (CGRP) stimulated CLR endocytosis and activated protein kinase C (PKC) in the cytosol and extracellular signal regulated kinase (ERK) in the cytosol and nucleus. Inhibitors of clathrin and dynamin prevented CLR endocytosis and activation of cytosolic PKC and nuclear ERK, which derive from endosomal CLR. A cholestanol-conjugated antagonist, CGRP8–37, accumulated in CLR-containing endosomes and selectively inhibited CLR signaling in endosomes. CGRP caused sustained excitation of neurons in slices of rat spinal cord. Inhibitors of dynamin, ERK, and PKC suppressed persistent neuronal excitation. CGRP8–37–cholestanol, but not unconjugated CGRP8–37, prevented sustained neuronal excitation. When injected intrathecally to mice, CGRP8–37–cholestanol inhibited nociceptive responses to intraplantar injection of capsaicin, formalin, or complete Freund’s adjuvant more effectively than unconjugated CGRP8–37. Our results show that CLR signals from endosomes to control pain transmission and identify CLR in endosomes as a therapeutic target for pain. Thus, GPCRs function not only at the plasma membrane but also in endosomes to control complex processes in vivo. Endosomal GPCRs are a drug target that deserve further attention. © 2017, National Academy of Sciences. All rights reserved. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | unknown |
| تدمد: | 0027-8424 |
| العلاقة: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85033680288&doi=10.1073%2fpnas.1706656114&partnerID=40&md5=3e2db7f21c0a28c3ac334f0fe56198a3Test; Proceedings of the National Academy of Sciences; Volume 114; Issue 46; Pagination 12309-12314; https://nottingham-repository.worktribe.com/file/1311753/1/Yarwood%20et%20al%20PNASTest |
| DOI: | 10.1073/pnas.1706656114 |
| الإتاحة: | https://doi.org/10.1073/pnas.1706656114Test https://nottingham-repository.worktribe.com/file/1311753/1/Yarwood%20et%20al%20PNASTest |
| حقوق: | openAccess |
| رقم الانضمام: | edsbas.E7D2A4A7 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 00278424 |
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| DOI: | 10.1073/pnas.1706656114 |