Targeting the I Ks Channel PKA Phosphorylation Axis to Restore Its Function in High-Risk LQT1 Variants.

Autor:	Zhong L; Dr. Neher's 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.).; 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.)., Yan Z; Dr. Neher's 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.).; 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.)., Jiang D; Dr. Neher's 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.).; 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.)., Weng KC; 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.)., Ouyang Y; Dr. Neher's 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.).; 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.)., Zhang H; Dr. Neher's 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.).; 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.)., Lin X; Dr. Neher's 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.).; 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.)., Xiao C; Dr. Neher's 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.).; 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.)., Yang H; Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University (H.Y.)., Yao J; State Key Laboratory of Virology, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, TaiKang Center for Life and Medical Sciences, Frontier Science Center for Immunology and Metabolism, Wuhan University, China (J.Y.)., Kang X; Key Laboratory of Medical Electrophysiology, Ministry of Education of China, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease and the Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China (X.K.).; Department of Neurosurgery, the Affiliated Hospital of Southwest Medical University, Luzhou, China (X.K.).; College of Life Sciences, Liaocheng University, China (X.K.)., Wang C; Dr. Neher's 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.).; Department of Neurology, First Affiliated Hospital, Neuroscience Research Center, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, China (C.W.)., Huang C; 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.)., Shen B; Dr. Neher's 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.).; 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.)., Chung SK; Dr. Neher's 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.).; 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.)., Jiang ZH; Dr. Neher's 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.).; 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.)., Zhu W; Cardiovascular Medicine Division and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (W.Z.)., Neher E; Dr. Neher's 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.).; 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.)., Silva JR; 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.)., Hou P; Dr. Neher's 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.).; 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.).
Jazyk:	angličtina
Zdroj:	Circulation research [Circ Res] 2024 Sep 13; Vol. 135 (7), pp. 722-738. Date of Electronic Publication: 2024 Aug 21.
DOI:	10.1161/CIRCRESAHA.124.325009
Abstrakt:	Background: The KCNQ1+KCNE1 (I Ks ) potassium channel plays a crucial role in cardiac adaptation to stress, in which β-adrenergic stimulation phosphorylates the I Ks 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 Ks channel phosphorylation and channel function, as well as why high-risk LQT1 mutations lose cAMP sensitivity, remain unclear. Methods: 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 Ks channels. The clinical phenotypic penetrance of each LQT1 mutation was analyzed as a metric for assessing their clinical risk. The patient-specific-induced pluripotent stem-cell model was used to test mechanistic findings in physiological conditions. Results: By systematically elucidating mechanisms of a series of LQT1 variants that lack cAMP sensitivity, we identified molecular determinants of I Ks channel regulation by phosphorylation. These key residues are distributed across the N-terminus of KCNQ1 extending to the central pore region of I Ks . We refer to this pattern as the I Ks channel PKA phosphorylation axis. Next, by examining LQT1 variants from clinical databases containing 10 579 LQT1 carriers, we found that the distribution of the most high-penetrance LQT1 variants extends across the I Ks 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-derived cardiomyocytes, where ML277 remarkably alleviates the beating abnormalities. Conclusions: Our findings not only elucidate the molecular mechanism of PKA-dependent I Ks channel phosphorylation but also provide an effective antiarrhythmic strategy for patients with high-risk LQT1 variants. Competing Interests: None.
Databáze:	MEDLINE
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