{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T07:44:57Z","timestamp":1790495097888,"version":"4.1.0"},"reference-count":50,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2016,3,23]],"date-time":"2016-03-23T00:00:00Z","timestamp":1458691200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2016,3,23]],"date-time":"2016-03-23T00:00:00Z","timestamp":1458691200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2016,6,15]]},"abstract":"<jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>\n                            Two functional abnormalities of cystic fibrosis transmembrane conductance regulator (CFTR), a 25% reduction of the single\u2010channel conductance (\n                            <jats:italic>g<\/jats:italic>\n                            ) and a \u223c13\u2010fold lower open probability (\n                            <jats:italic>P<\/jats:italic>\n                            <jats:sub>o<\/jats:sub>\n                            ), were found with the R117H mutation that is associated with mild forms of cystic fibrosis.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            Characterizations of the gating defects of R117H\u2010CFTR led to the conclusion that the mutation decreases\n                            <jats:italic>P<\/jats:italic>\n                            <jats:sub>o<\/jats:sub>\n                            by perturbing the gating conformational changes in CFTR's transmembrane domains (TMDs) without altering the function of the nucleotide binding domains (NBDs).\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Nonetheless, gating of the R117H\u2010CFTR can be improved by a variety of pharmacological reagents supposedly acting on NBDs such as ATP analogues, or TMDs (e.g. VX\u2010770 or nitrate). These reagents potentiate synergistically R117H\u2010CFTR gating to a level that allows accurate assessments of its gating deficits.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Our studies not only elucidate the mechanism underpinning gating dysfunction of R117H\u2010CFTR, but also provide a mechanistic understanding of how VX\u2010770 ameliorates the gating defects in the R117H mutant.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>\n                      Cystic fibrosis (CF) is caused by loss\u2010of\u2010function mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene encoding a phosphorylation\u2010activated, but ATP\u2010gated chloride channel. In the current study, we investigated the mechanism responsible for the gating defects manifested in R117H\u2010CFTR, an arginine\u2010to\u2010histidine substitution at position 117 of CFTR that is associated with mild forms of CF. We confirmed previous findings of a 25% decrease of the single\u2010channel conductance (\n                      <jats:italic>g<\/jats:italic>\n                      ) in R117H\u2010CFTR, but found a \u223c13\u2010fold lower open probability (\n                      <jats:italic>P<\/jats:italic>\n                      <jats:sub>o<\/jats:sub>\n                      ). This dramatic gating deficit is not due to dysfunctional nucleotide binding domains (NBDs) as the mutation does not alter the apparent affinity for ATP, and the mutant channels respond to ATP analogues in a similar manner as wild\u2010type CFTR. Furthermore, once ATP hydrolysis is abolished, the R117H mutant can be trapped in a prolonged \u2018burst opening\u2019 conformation that is proposed to be equipped with a stable NBD dimer. On the other hand, our results support the conclusion that the R117H mutation decreases\n                      <jats:italic>P<\/jats:italic>\n                      <jats:sub>o<\/jats:sub>\n                      by perturbing the gating conformational changes in CFTR's transmembrane domains as even when NBDs are kept at a dimerized configuration,\n                      <jats:italic>P<\/jats:italic>\n                      <jats:sub>o<\/jats:sub>\n                      is reduced by \u223c10\u2010fold. Moreover, our data demonstrate that a synergistic improvement of R117H\u2010CFTR function can be accomplished with a combined regiment of VX\u2010770 (Ivacaftor), nitrate ion (NO\n                      <jats:sub>3<\/jats:sub>\n                      <jats:sup>\u2212<\/jats:sup>\n                      ) and\n                      <jats:italic>N<\/jats:italic>\n                      <jats:sup>6<\/jats:sup>\n                      \u2010(2\u2010phenylethyl)\u20102\u2032\u2010deoxy\u2010ATP (d\u2010PATP), which almost completely rectifies the gating defect of R117H\u2010CFTR. Clinical implications of our results are discussed.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1113\/jp271723","type":"journal-article","created":{"date-parts":[[2016,2,5]],"date-time":"2016-02-05T05:40:12Z","timestamp":1454650812000},"page":"3227-3244","source":"Crossref","is-referenced-by-count":35,"title":["On the mechanism of gating defects caused by the R117H mutation in cystic fibrosis transmembrane conductance regulator"],"prefix":"10.1113","volume":"594","author":[{"given":"Ying\u2010Chun","family":"Yu","sequence":"first","affiliation":[{"name":"Dalton Cardiovascular Research Center University of Missouri\u2010Columbia  MO 65211 USA"},{"name":"Department of Medical Pharmacology and Physiology University of Missouri\u2010Columbia  MO 65211 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiro","family":"Sohma","sequence":"additional","affiliation":[{"name":"Dalton Cardiovascular Research Center University of Missouri\u2010Columbia  MO 65211 USA"},{"name":"Department of Pharmacology Keio University School of Medicine  Shinjuku Tokyo 160\u20108582 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzyh\u2010Chang","family":"Hwang","sequence":"additional","affiliation":[{"name":"Dalton Cardiovascular Research Center University of Missouri\u2010Columbia  MO 65211 USA"},{"name":"Department of Medical Pharmacology and Physiology University of Missouri\u2010Columbia  MO 65211 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,3,23]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.201010480"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.200409227"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.200409228"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M709417200"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.200609667"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.35.20466"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(90)90148-8"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(00)76636-7"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.201210954"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.201311122"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/354526a0"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI115582"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.113332"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1040-7952(99)80006-8"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature04712"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1420676112"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.31.21873"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M011017200"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1152\/physiol.00026.2012"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1215982110"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2010.202861"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.201210834"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.13-227330"},{"key":"e_1_2_6_25_1","doi-asserted-by":"crossref","first-page":"21592","DOI":"10.1016\/S0021-9258(20)80582-1","article-title":"The \u0394F508 mutation decreases the stability of cystic fibrosis transmembrane conductance regulator in the plasma membrane. Determination of functional half\u2010lives on transfected cells","volume":"268","author":"Lukacs GL","year":"1993","journal-title":"J Biol Chem"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7601373"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.092684"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M803185200"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(15)00201-5"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.41.25184"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1096\/fasebj.4.10.2197151"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1105185"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.2475911"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1148\/rg.263055101"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M407434200"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0005-2736(99)00163-7"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/362160a0"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.201010399"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.200810186"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0904709106"},{"key":"e_1_2_6_41_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1105787108"},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature03313"},{"key":"e_1_2_6_43_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1409547"},{"key":"e_1_2_6_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90353-R"},{"key":"e_1_2_6_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(95)70157-5"},{"key":"e_1_2_6_46_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.201411272"},{"key":"e_1_2_6_47_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-008-0521-6"},{"key":"e_1_2_6_48_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.2001.0435f.x"},{"key":"e_1_2_6_49_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2005.095083"},{"key":"e_1_2_6_50_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.200609622"},{"key":"e_1_2_6_51_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.ge.29.120195.004021"}],"container-title":["The Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1113%2FJP271723","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP271723","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/full-xml\/10.1113\/JP271723","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP271723","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T04:50:22Z","timestamp":1775796622000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/JP271723"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,3,23]]},"references-count":50,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2016,6,15]]}},"alternative-id":["10.1113\/JP271723"],"URL":"https:\/\/doi.org\/10.1113\/jp271723","archive":["Portico"],"relation":{},"ISSN":["0022-3751","1469-7793"],"issn-type":[{"value":"0022-3751","type":"print"},{"value":"1469-7793","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,3,23]]}}}