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TRPM5-mediated calcium uptake regulates mucin secretion from human colon goblet cells
Mitrovic, Sandra; Nogueira, Cristina; Cantero Recasens, Gerard, 1984-; Kiefer, Kerstin; Fernández-Fernández, José Manuel; Popoff, Jean-François; Casano, Laetitia; Bard, Frederic A.; Gómez, Raul; Valverde, M. A. (Miguel Ángel), 1963-; Malhotra, Vivek
Mucin 5AC (MUC5AC) is secreted by goblet cells of the respiratory tract and, surprisingly, also expressed de novo in mucus secreting cancer lines. siRNA-mediated knockdown of 7343 human gene products in a human colonic cancer goblet cell line (HT29-18N2) revealed new proteins, including a Ca(2+)-activated channel TRPM5, for MUC5AC secretion. TRPM5 was required for PMA and ATP-induced secretion of MUC5AC from the post-Golgi secretory granules. Stable knockdown of TRPM5 reduced a TRPM5-like current and ATP-mediated Ca(2+) signal. ATP-induced MUC5AC secretion depended strongly on Ca(2+) influx, which was markedly reduced in TRPM5 knockdown cells. The difference in ATP-induced Ca(2+) entry between control and TRPM5 knockdown cells was abrogated in the absence of extracellular Ca(2+) and by inhibition of the Na(+)/Ca(2+) exchanger (NCX). Accordingly, MUC5AC secretion was reduced by inhibition of NCX. Thus TRPM5 activation by ATP couples TRPM5-mediated Na(+) entry to promote Ca(2+) uptake via an NCX to trigger MUC5AC secretion
Funding: Vivek Malhotra: Sandler Foundation for Asthma Research; Institucio Catalana de Recerca i Estudis Avancats (ICREA); Plan Nacional (BFU2008-00414); Consolider (CSD2009-00016); Agencia de Gestio d’ Ajuts Universitaris i de Recerca (AGAUR) Grups de Recerca Emergents (SGR2009-1488); European Research Council (268692). Miguel A. Valverde: ICREA Academia Award; Spanish Ministry of Economy and Competitiveness (SAF2012-38140); Fondo de Investigacion Sanitaria (Red HERACLES RD12/0042/0014); FEDER Funds; SGR09-1369. José M. Fernández Fernández: Spanish Ministry of Economy and Competitiveness (SAF2012-31089)
13-05-2014
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© Sandra Mitrovic et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
http://creativecommons.org/licenses/by/3.0/
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info:eu-repo/semantics/publishedVersion
eLife
         

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