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Adult Wistar rat primary sensory neurons grown at physiological pH 7.4, then either kept at pH 7.4 or challenged for 30 min in pH 6.5 medium, provided a model of acidosis. Nonpermeabilizing trkA immunofluorescence revealed a significant increase in trkA mobilization to the plasma membrane from intracellular stores in response to proton challenge. This was confirmed using a surface protein biotinylation assay and Brefeldin A disruption of the rough endoplasmic reticulum-Golgi-<jats:italic>trans<\/jats:italic>-Golgi network. Mobilization of trkA to the membrane at pH 6.5 was abolished in neurons treated with the acid-sensitive ion channel blocker, amiloride. While elevated levels of NGF-independent trkA phosphorylation occurred at pH 6.5 alone, the level of activation was significantly increased in response to NGF challenge. Exposure of sensory neurons to pH 6.5 medium also resulted in strong calcium (Ca<jats:sup>2+<\/jats:sup>) transients that were reversible upon reintroduction to physiological pH. The pH 6.5-induced mobilization of trkA to the membrane was Ca<jats:sup>2+<\/jats:sup>dependent, as BAPTA-AM Ca<jats:sup>2+<\/jats:sup>chelation abrogated the response. Interestingly, KCl-induced depolarization was sufficient to induce mobilization of trkA to the cell surface at pH 7.4, but did not augment the response to pH 6.5. In conclusion, increased mobilization of trkA to neuronal membranes in response to either acidosis or neuronal depolarization provides two novel mechanisms by which sensory neurons can rapidly sensitize to NGF and has important implications for inflammatory pain states.<\/jats:p>","DOI":"10.1523\/jneurosci.4408-12.2013","type":"journal-article","created":{"date-parts":[[2013,5,8]],"date-time":"2013-05-08T16:38:10Z","timestamp":1368031090000},"page":"8202-8215","source":"Crossref","is-referenced-by-count":13,"title":["Extracellular pH and Neuronal Depolarization Serve as Dynamic Switches to Rapidly Mobilize trkA to the Membrane of Adult Sensory Neurons"],"prefix":"10.1523","volume":"33","author":[{"given":"Geoffrey E.","family":"Bray","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengxin","family":"Ying","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Landon D.","family":"Baillie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruiling","family":"Zhai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean J.","family":"Mulligan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie M.K.","family":"Verge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"393","published-online":{"date-parts":[[2013,5,8]]},"reference":[{"key":"2023041304041258000_33.19.8202.1","first-page":"2018","article-title":"Tissue and intracellular pH in normal periarticular soft tissue and during different phases of antigen induced arthritis in the rat","volume":"26","author":"Andersson","year":"1999","journal-title":"J Rheumatol"},{"key":"2023041304041258000_33.19.8202.2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1542-09.2009"},{"key":"2023041304041258000_33.19.8202.3","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.1995.tb01143.x"},{"key":"2023041304041258000_33.19.8202.4","doi-asserted-by":"publisher","DOI":"10.1023\/B:NEUR.0000021903.24849.6c"},{"key":"2023041304041258000_33.19.8202.5","doi-asserted-by":"crossref","first-page":"7417","DOI":"10.1523\/JNEUROSCI.20-19-07417.2000","article-title":"Activity-dependent release of endogenous brain-derived neurotrophic factor from primary sensory neurons detected by ELISA in situ","volume":"20","author":"Balkowiec","year":"2000","journal-title":"J Neurosci"},{"key":"2023041304041258000_33.19.8202.6","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1002\/j.1460-2075.1987.tb04835.x","article-title":"Cellular localization of nerve growth factor synthesis by in situ hybridization","volume":"6","author":"Bandtlow","year":"1987","journal-title":"EMBO J"},{"key":"2023041304041258000_33.19.8202.7","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(02)01103-0"},{"key":"2023041304041258000_33.19.8202.8","doi-asserted-by":"crossref","first-page":"7325","DOI":"10.1523\/JNEUROSCI.20-19-07325.2000","article-title":"NGF signals through TrkA to increase clathrin at the plasma membrane and enhance clathrin-mediated membrane trafficking","volume":"20","author":"Beattie","year":"2000","journal-title":"J Neurosci"},{"key":"2023041304041258000_33.19.8202.9","doi-asserted-by":"publisher","DOI":"10.1126\/science.1321502"},{"key":"2023041304041258000_33.19.8202.10","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2008.05609.x"},{"key":"2023041304041258000_33.19.8202.11","doi-asserted-by":"publisher","DOI":"10.1016\/0003-2697(76)90527-3"},{"key":"2023041304041258000_33.19.8202.12","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.81.3.555"},{"key":"2023041304041258000_33.19.8202.13","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1981.tb05244.x"},{"key":"2023041304041258000_33.19.8202.14","doi-asserted-by":"publisher","DOI":"10.1038\/35082088"},{"key":"2023041304041258000_33.19.8202.15","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0713-07.2007"},{"key":"2023041304041258000_33.19.8202.16","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2008.213"},{"key":"2023041304041258000_33.19.8202.17","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.15.8963"},{"key":"2023041304041258000_33.19.8202.18","doi-asserted-by":"crossref","first-page":"9189","DOI":"10.1016\/S0021-9258(18)48066-0","article-title":"Voltage-dependent activation and inactivation of calcium channels in PC12 cells. 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