{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T04:12:17Z","timestamp":1791951137220,"version":"4.3.4"},"reference-count":96,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","license":[{"start":{"date-parts":[[2024,9,13]],"date-time":"2024-09-13T00:00:00Z","timestamp":1726185600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2024,9,13]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>\n              The KCNQ1+KCNE1 (I\n              <jats:sub>Ks<\/jats:sub>\n              ) potassium channel plays a crucial role in cardiac adaptation to stress, in which \u03b2-adrenergic stimulation phosphorylates the I\n              <jats:sub>Ks<\/jats:sub>\n              channel through the cyclic adenosine monophosphate (cAMP)\/PKA (protein kinase A) pathway. Phosphorylation increases the channel current and accelerates repolarization to adapt to an increased heart rate. Variants in KCNQ1 can cause long-QT syndrome type 1 (LQT1), and those with defective cAMP effects predispose patients to the highest risk of cardiac arrest and sudden death. However, the molecular connection between I\n              <jats:sub>Ks<\/jats:sub>\n              channel phosphorylation and channel function, as well as why high-risk LQT1 mutations lose cAMP sensitivity, remain unclear.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>\n              Regular patch clamp and voltage clamp fluorometry techniques were utilized to record pore opening and voltage sensor movement of wild-type and mutant KCNQ1\/I\n              <jats:sub>Ks<\/jats:sub>\n              channels. The clinical phenotypic penetrance of each LQT1 mutation was analyzed as a metric for assessing their clinical risk. The patient-specific\u2013induced pluripotent stem-cell model was used to test mechanistic findings in physiological conditions.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              By systematically elucidating mechanisms of a series of LQT1 variants that lack cAMP sensitivity, we identified molecular determinants of I\n              <jats:sub>Ks<\/jats:sub>\n              channel regulation by phosphorylation. These key residues are distributed across the N-terminus of KCNQ1 extending to the central pore region of I\n              <jats:sub>Ks<\/jats:sub>\n              . We refer to this pattern as the I\n              <jats:sub>Ks<\/jats:sub>\n              channel PKA phosphorylation axis. Next, by examining LQT1 variants from clinical databases containing 10\u2009579 LQT1 carriers, we found that the distribution of the most high-penetrance LQT1 variants extends across the I\n              <jats:sub>Ks<\/jats:sub>\n              channel PKA phosphorylation axis, demonstrating its clinical relevance. Furthermore, we found that a small molecule, ML277, which binds at the center of the phosphorylation axis, rescues the defective cAMP effects of multiple high-risk LQT1 variants. This finding was then tested in high-risk patient-specific induced pluripotent stem cell\u2013derived cardiomyocytes, where ML277 remarkably alleviates the beating abnormalities.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>\n              Our findings not only elucidate the molecular mechanism of PKA-dependent I\n              <jats:sub>Ks<\/jats:sub>\n              channel phosphorylation but also provide an effective antiarrhythmic strategy for patients with high-risk LQT1 variants.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.124.325009","type":"journal-article","created":{"date-parts":[[2024,8,22]],"date-time":"2024-08-22T01:03:11Z","timestamp":1724288591000},"page":"722-738","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":13,"title":["Targeting the I\n            <sub>Ks<\/sub>\n            Channel PKA Phosphorylation Axis to Restore Its Function in High-Risk LQT1 Variants"],"prefix":"10.1161","volume":"135","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-2191-2521","authenticated-orcid":true,"given":"Ling","family":"Zhong","sequence":"first","affiliation":[{"name":"Dr. Neher\u2019s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao SAR, China (L.Z., Z.Y., D.J., Y.O., H.Z., X.L., C.X., C.H., B.S., S.K.C., Z.-H.J., E.N., P.H.)."},{"name":"Macau University of Science and Technology Zhuhai MUST Science and Technology Research Institute. Zhuhai, Guangdong, China (L.Z., Z.Y., D.J., Y.O., H.Z., X.L., C.X., C.H., B.S., S.K.C., Z.-H.J., E.N., P.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4416-9743","authenticated-orcid":true,"given":"Zhenzhen","family":"Yan","sequence":"additional","affiliation":[{"name":"Dr. Neher\u2019s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao SAR, China (L.Z., Z.Y., D.J., Y.O., H.Z., X.L., C.X., C.H., B.S., S.K.C., Z.-H.J., E.N., P.H.)."},{"name":"Macau University of Science and Technology Zhuhai MUST Science and Technology Research Institute. Zhuhai, Guangdong, China (L.Z., Z.Y., D.J., Y.O., H.Z., X.L., C.X., C.H., B.S., S.K.C., Z.-H.J., E.N., P.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-2146-7798","authenticated-orcid":true,"given":"Dexiang","family":"Jiang","sequence":"additional","affiliation":[{"name":"Dr. Neher\u2019s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao SAR, China (L.Z., Z.Y., D.J., Y.O., H.Z., X.L., C.X., C.H., B.S., S.K.C., Z.-H.J., E.N., P.H.)."},{"name":"Macau University of Science and Technology Zhuhai MUST Science and Technology Research Institute. Zhuhai, Guangdong, China (L.Z., Z.Y., D.J., Y.O., H.Z., X.L., C.X., C.H., B.S., S.K.C., Z.-H.J., E.N., P.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0549-755X","authenticated-orcid":true,"given":"Kuo-Chan","family":"Weng","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Disorders, Cardiac Bioelectricity and Arrhythmia Center, Washington University, St. Louis, MO (K.-C.W., J.R.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7735-5334","authenticated-orcid":true,"given":"Yue","family":"Ouyang","sequence":"additional","affiliation":[{"name":"Dr. Neher\u2019s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao SAR, China (L.Z., Z.Y., D.J., Y.O., H.Z., X.L., C.X., C.H., B.S., S.K.C., Z.-H.J., E.N., P.H.)."},{"name":"Macau University of Science and Technology Zhuhai MUST Science and Technology Research Institute. 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Zhuhai, Guangdong, China (L.Z., Z.Y., D.J., Y.O., H.Z., X.L., C.X., C.H., B.S., S.K.C., Z.-H.J., E.N., P.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0261-9794","authenticated-orcid":true,"given":"Xiaoqing","family":"Lin","sequence":"additional","affiliation":[{"name":"Dr. Neher\u2019s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao SAR, China (L.Z., Z.Y., D.J., Y.O., H.Z., X.L., C.X., C.H., B.S., S.K.C., Z.-H.J., E.N., P.H.)."},{"name":"Macau University of Science and Technology Zhuhai MUST Science and Technology Research Institute. 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