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Activation of nicotinic acetylcholine receptors (nAChRs) elicits Ca\n                    <jats:sup>2+<\/jats:sup>\n                    influx that varies in magnitude between different nAChR subtypes. Normal differentiation of KCs is associated with sequential expression of the nAChR subtypes with increasing Ca\n                    <jats:sup>2+<\/jats:sup>\n                    permeability, such as \u03b15\u2010containing \u03b13 nAChR and \u03b17 nAChR. Exposure to environmental tobacco smoke (ETS) or an equivalent concentration of nicotine accelerated by severalfold the \u03b15 and \u03b1 7 expression in KCs, which could be abolished by mecamylamine and \u03b1\u2010bungarotoxin with different efficacies, suggesting the following sequence of auto regulation of the expression of nAChR subtypes: \u03b13(\u03b22\/\u03b24) &gt; \u03b13(\u03b22\/\u03b24)\u03b15 &gt; \u03b17 &gt; \u03b17. This conjecture was corroborated by results of quantitative assays of subunit mRNA and protein levels, using nAChR\u2010 specific pharmacologic antagonists and small interfering RNAs. The genomic effects of ETS and nicotine involved the transcription factor GATA\u20102 that showed a multifold increase in quantity and activity in exposed KCs. Using protein kinase inhibitors and dominant negative and constitutively active constructs, we charac terized the principal signaling cascades mediating a switch in the nAChR subtype. Cumulative results indi cated that the \u03b13(\u03b22\/\u03b24) to \u03b13(\u03b22\/\u03b14)\u03b15 nAChR tran sition predominantly involved protein kinase C, \u03b13(\u03b22\/ \u03b24)\u03b15 to \u03b17 nAChR transition\u2014Ca\n                    <jats:sup>2+<\/jats:sup>\n                    \/calmodulin\u2010 dependent protein kinase II and p38 MAPK, and \u03b17 self\u2010up\u2010regulatio\u2014the p38 MAPK\/Akt pathway, and JAK\u20102. These results provide a mechanistic insight into the genomic effects of ETS and nicotine on KCs and characterize signaling pathways mediating autoregulation of stepwise overexpression of nAChR subtypes with increasing Ca\n                    <jats:sup>2+<\/jats:sup>\n                    permeability in exposed cells. These observations have salient clinical implications, because a switch in the nAChR subunit composition can bring about a corresponding switch in receptor function, leading to profound pathobiologic effects ob served in KCs exposed to tobacco products.\u2014Arredondo, J., Chernyavsky, A. I., Jolkovsky, D. L., Pinkerton, K. E., Grando, S. A. Receptor\u2010mediated tobacco toxicity: acceleration of sequential expression of \u03b15 and \u03b17 nicotinic receptor subunits in oral keratinocytes exposed to cigarette smoke.\n                    <jats:italic>FASEB J<\/jats:italic>\n                    . 22, 1356\u20131368 (2008)\n                  <\/jats:p>","DOI":"10.1096\/fj.07-9965.com","type":"journal-article","created":{"date-parts":[[2008,4,30]],"date-time":"2008-04-30T17:58:23Z","timestamp":1209578303000},"page":"1356-1368","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":73,"title":["Receptor\u2010mediated tobacco toxicity: acceleration of sequential expression of \u03b15 and \u03b17 nicotinic receptor subunits in oral keratinocytes exposed to cigarette smoke"],"prefix":"10.1096","volume":"22","author":[{"given":"Juan","family":"Arredondo","sequence":"first","affiliation":[{"name":"Department of Dermatology University of California Irvine California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander I.","family":"Chernyavsky","sequence":"additional","affiliation":[{"name":"Department of Dermatology University of California Irvine California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David L.","family":"Jolkovsky","sequence":"additional","affiliation":[{"name":"Section of Periodontics School of Dentistry University of California Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kent E.","family":"Pinkerton","sequence":"additional","affiliation":[{"name":"Center for Health and the Environment University of California Davis California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergei A.","family":"Grando","sequence":"additional","affiliation":[{"name":"Department of Dermatology University of California Irvine California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2007,11,29]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0887-2333(01)00047-9"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1159\/000066247"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/0030-4220(93)90145-T"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0714.1982.tb00180.x"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0714.1989.tb01349.x"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0142(19891001)64:7<1527::AID-CNCR2820640728>3.0.CO;2-N"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0714.1982.tb00162.x"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.3322\/canjclin.57.1.43"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.jid.5700151"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)62281-X"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2007.01.013"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.06-6191com"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.4161\/cbt.5.5.2601"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1177\/00220345000790040901"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)64651-2"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-0348-7445-8_6"},{"key":"e_1_2_6_18_1","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1242\/jcs.114.6.1189","article-title":"Programmed cell death of keratinocytes culminates in apoptotic secretion of a humectant upon secretagogue action of acetylcholine","volume":"114","author":"Nguyen V. 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