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Small\u2010molecule drugs are being developed to correct \u0394F508 CFTR. To understand correction mechanisms and the consequences of synonymous mutations, we analyzed the effect of mechanistically distinct correctors, corrector 4a (C4) and lumacaftor (VX\u2010809), on I507\u2010ATT and I507\u2010ATC \u0394F508 CFTR biogenesis and function. C4 stabilized I507\u2010ATT \u0394F508 CFTR band B, but without considerable biochemical and functional correction. VX\u2010809 biochemically corrected ~10% of both of the variants, leading to stable, forskolin+3\u2010isobutyl\u20101\u2010methylxanthine (IBMX)\u2010activated whole\u2010cell currents in the presence of the corrector. Omitting VX\u2010809 during whole\u2010cell recordings led to a spontaneous decline of the currents, suggesting posttranslational stabilization by VX\u2010809. Treatment of cells with the C4+VX\u2010809 combination resulted in enhanced rescue and 2\u2010fold higher forskolin+IBMX\u2010activated currents of both I507\u2010ATT and I507\u2010ATC \u0394F508 CFTR, compared with VX\u2010809 treatment alone. The lack of an effect of C4 on I507\u2010ATC \u0394F508 CFTR, but its additive effect in combination with VX\u2010809, implies that C4 acted on VX\u2010809\u2010modified I507\u2010ATC \u0394F508 CFTR. Our results suggest that binding of C4 and VX\u2010809 to \u0394F508 CFTR is conformation specific and provide evidence that synonymous mutations can alter the drug sensitivity of proteins.\u2014Bali, V., Lazrak, A., Guroji, P., Fu, L., Matalon, S., Bebok, Z. A synonymous codon change alters the drug sensitivity of \u0394F508 cystic fibrosis transmembrane conductance regulator.\n                    <jats:italic>FASEB J.<\/jats:italic>\n                    30, 201\u2010213 (2016).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.15-273714","type":"journal-article","created":{"date-parts":[[2015,9,3]],"date-time":"2015-09-03T23:18:49Z","timestamp":1441322329000},"page":"201-213","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["A synonymous codon change alters the drug sensitivity of \u0394F508 cystic fibrosis transmembrane conductance regulator"],"prefix":"10.1096","volume":"30","author":[{"given":"Vedrana","family":"Bali","sequence":"first","affiliation":[{"name":"Department of Cell, Developmental, and Integrative Biology University of Alabama at Birmingham Birmingham Alabama USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ahmed","family":"Lazrak","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Perioperative Medicine University of Alabama at Birmingham Birmingham Alabama USA"},{"name":"The Lung Injury and Repair Research Center University of Alabama at Birmingham Birmingham Alabama USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Purushotham","family":"Guroji","sequence":"additional","affiliation":[{"name":"Department of Cell, Developmental, and Integrative Biology University of Alabama at Birmingham Birmingham Alabama USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lianwu","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Cell, Developmental, and Integrative Biology University of Alabama at Birmingham Birmingham Alabama USA"},{"name":"The Cystic Fibrosis Research Center University of Alabama at Birmingham Birmingham Alabama USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sadis","family":"Matalon","sequence":"additional","affiliation":[{"name":"Department of Cell, Developmental, and Integrative Biology University of Alabama at Birmingham Birmingham Alabama USA"},{"name":"Department of Anesthesiology and Perioperative Medicine University of Alabama at Birmingham Birmingham Alabama USA"},{"name":"The Lung Injury and Repair Research Center University of Alabama at Birmingham Birmingham Alabama USA"},{"name":"The Cystic Fibrosis Research Center University of Alabama at Birmingham Birmingham Alabama USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zsuzsanna","family":"Bebok","sequence":"additional","affiliation":[{"name":"Department of Cell, Developmental, and Integrative Biology University of Alabama at Birmingham Birmingham Alabama USA"},{"name":"The Lung Injury and Repair Research Center University of Alabama at Birmingham Birmingham Alabama USA"},{"name":"The Cystic Fibrosis Research Center University of Alabama at Birmingham Birmingham Alabama USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2015,9,3]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/0005-2787(66)90198-5","article-title":"Degeneracy in the amino acid code","volume":"119","author":"Jones O. 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