The Experts below are selected from a list of 2589 Experts worldwide ranked by ideXlab platform
Gea-ny Tseng - One of the best experts on this subject based on the ideXlab platform.
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Gating-Related Molecular Motions in the Extracellular Domain of the I_Ks Channel: Implications for I_Ks Channelopathy
The Journal of Membrane Biology, 2011Co-Authors: Yuhong Wang, Kai-ling Hsu, Xulin Xu, Mei Zhang, Min Jiang, Gea-ny TsengAbstract:Cardiac slow delayed rectifier (I_Ks) channel complex consists of KCNQ1 channel and KCNE1 auxiliary subunits. The extracellular juxtamembranous region of KCNE1 is an unstructured loop that contacts multiple KCNQ1 positions in a gating-state-dependent manner. Congenital Arrhythmia-related mutations have been identified in the extracellular S1–S2 linker of KCNQ1. These mutations manifest abnormal phenotypes only when coexpressed with KCNE1, pointing to the importance of proper KCNQ1/KCNE1 interactions here in I_Ks channel function. We investigate the interactions between the KCNE1 loop (positions 36–47) and KCNQ1 S1–S2 linker (positions 140–148) by means of disulfide trapping and voltage clamp techniques. During transitions among the resting-state conformations, KCNE1 positions 36–43 make contacts with KCNQ1 positions 144, 145, and 147 in a parallel fashion. During conformational changes in the activated state, KCNE1 position 40 can make contacts with all three KCNQ1 positions, while the neighboring KCNE1 positions (36, 38, 39, and 41) can make contact with KCNQ1 position 147. Furthermore, KCNQ1 positions 143 and 146 are high-impact positions that cannot tolerate cysteine substitution. To maintain the proper I_Ks channel function, position 143 requires a small side chain with a hydroxyl group, and position 146 requires a negatively charged side chain. These data and the proposed molecular motions provide insights into the mechanisms by which mutations in the extracellular juxtamembranous region of the I_Ks channel impair its function.
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Gating-related molecular motions in the extracellular domain of the IKs channel: implications for IKs channelopathy.
The Journal of membrane biology, 2010Co-Authors: Yuhong Wang, Kai-ling Hsu, Mei Zhang, Min Jiang, Gea-ny TsengAbstract:Cardiac slow delayed rectifier (IKs) channel complex consists of KCNQ1 channel and KCNE1 auxiliary subunits. The extracellular juxtamembranous region of KCNE1 is an unstructured loop that contacts multiple KCNQ1 positions in a gating-state-dependent manner. Congenital Arrhythmia-related mutations have been identified in the extracellular S1–S2 linker of KCNQ1. These mutations manifest abnormal phenotypes only when coexpressed with KCNE1, pointing to the importance of proper KCNQ1/KCNE1 interactions here in IKs channel function. We investigate the interactions between the KCNE1 loop (positions 36–47) and KCNQ1 S1–S2 linker (positions 140–148) by means of disulfide trapping and voltage clamp techniques. During transitions among the resting-state conformations, KCNE1 positions 36–43 make contacts with KCNQ1 positions 144, 145, and 147 in a parallel fashion. During conformational changes in the activated state, KCNE1 position 40 can make contacts with all three KCNQ1 positions, while the neighboring KCNE1 positions (36, 38, 39, and 41) can make contact with KCNQ1 position 147. Furthermore, KCNQ1 positions 143 and 146 are high-impact positions that cannot tolerate cysteine substitution. To maintain the proper IKs channel function, position 143 requires a small side chain with a hydroxyl group, and position 146 requires a negatively charged side chain. These data and the proposed molecular motions provide insights into the mechanisms by which mutations in the extracellular juxtamembranous region of the IKs channel impair its function.
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Differential Molecular Motions of KCNE Subunits in the IKs Channel Complex Detected by Substituted Cysteine-Accessibility Test and Disulfide-Trapping Experiments
Biophysical Journal, 2010Co-Authors: Yuhong Wang, Kai-ling Hsu, Mei Zhang, Min Jiang, Gea-ny TsengAbstract:The IKs channel consists of a pore-forming KCNQ1 channel and auxiliary KCNE subunits: KCNE1 as the major determinant of IKs gating kinetics while KCNE2 as a regulator of IKs current amplitude. Knowledge about the structural basis of KCNQ1 modulation by these different KCNE subunits can help the design of KCNE-specific IKs modulators as antiarrhythmic agents. Recent studies showed that the extracellular-juxtamembranous region of KCNE1 could adopt highly flexible structures and make gating state-dependent contacts with the voltage-sensing domain (VSD) and pore-domain (PD) of KCNQ1. KCNQ1-KCNE1 interactions in this extracellular-juxtamembranous region are critical for the IKs channel function, as evidenced by Congenital Arrhythmia-associated mutations identified in this region. Whether KCNE2 can do the same is unclear. We systematically probe the functional role of the extracellular-juxtamembranous region of KCNE1 (positions 36-47) and KCNE2 (positions 39-50), using cysteine-scanning mutagenesis followed by cysteine-accessibility test and disulfide-trapping experiments. MTSET modification of KCNE1 40C-46C alters the voltage-dependence of IKs activation and, for 44C-46C, reduces the current amplitude. There is a gradient in MTSET modification rates, from fast-reacting (41C-42C) to slow-reacting (44C-46C), with 43C reporting state-dependent accessibility: fast-reacting in open-state & slow-reacting in closed-state. While extensive disulfide-bond partners are found between KCNE1 36C-43C and KCNQ1 144C-147C, no such disulfide-bond partners can be identified between the equivalent KCNE2 positions and KCNQ1 140C-148C. We propose that the KCNE transmembrane helices reside in the junction between VSDs and PD of the KCNQ1 channel, with a similar orientation (with respect to KCNQ1) and position (with respect to membrane bilayer). However, their extracellular-juxtamembranous regions can make differential contacts with KCNQ1, that contribute to their differential effects on the KCNQ1 channel function and provide an opportunity for the design of KCNE-specific IKs modulators.
Antoine Leenhardt - One of the best experts on this subject based on the ideXlab platform.
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defining the cellular phenotype of ankyrin b syndrome variants human ank2 variants associated with clinical phenotypes display a spectrum of activities in cardiomyocytes
Circulation, 2007Co-Authors: Peter J Mohler, Solena Le Scouarnec, John S Lowe, Lise Caron, Iwona Driskell, Jeanjacques Schott, Kris Norris, Pascale Guicheney, Isabelle Denjoy, Antoine LeenhardtAbstract:Background— Mutations in the ankyrin-B gene (ANK2) cause type 4 long-QT syndrome and have been described in kindreds with other Arrhythmias. The frequency of ANK2 variants in large populations and molecular mechanisms underlying the variability in the clinical phenotypes are not established. More importantly, there is no cellular explanation for the range of severity of cardiac phenotypes associated with specific ANK2 variants. Methods and Results— We performed a comprehensive screen of ANK2 in populations (control, Congenital Arrhythmia, drug-induced long-QT syndrome) of different ethnicities to discover unidentified ANK2 variants. We identified 7 novel nonsynonymous ANK2 variants; 4 displayed abnormal activity in cardiomyocytes. Including the 4 new variants, 9 human ANK2 loss-of-function variants have been identified. However, the clinical phenotypes associated with these variants vary strikingly, from no obvious phenotype to manifest long-QT syndrome and sudden death, suggesting that mutants confer a s...
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Defining the Cellular Phenotype of “Ankyrin-B Syndrome” Variants Human ANK2 Variants Associated With Clinical Phenotypes Display a Spectrum of Activities in Cardiomyocytes
Circulation, 2007Co-Authors: Peter J Mohler, Solena Le Scouarnec, John S Lowe, Lise Caron, Iwona Driskell, Jeanjacques Schott, Kris Norris, Pascale Guicheney, Isabelle Denjoy, Antoine LeenhardtAbstract:Background— Mutations in the ankyrin-B gene (ANK2) cause type 4 long-QT syndrome and have been described in kindreds with other Arrhythmias. The frequency of ANK2 variants in large populations and molecular mechanisms underlying the variability in the clinical phenotypes are not established. More importantly, there is no cellular explanation for the range of severity of cardiac phenotypes associated with specific ANK2 variants. Methods and Results— We performed a comprehensive screen of ANK2 in populations (control, Congenital Arrhythmia, drug-induced long-QT syndrome) of different ethnicities to discover unidentified ANK2 variants. We identified 7 novel nonsynonymous ANK2 variants; 4 displayed abnormal activity in cardiomyocytes. Including the 4 new variants, 9 human ANK2 loss-of-function variants have been identified. However, the clinical phenotypes associated with these variants vary strikingly, from no obvious phenotype to manifest long-QT syndrome and sudden death, suggesting that mutants confer a s...
Yuhong Wang - One of the best experts on this subject based on the ideXlab platform.
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Gating-Related Molecular Motions in the Extracellular Domain of the I_Ks Channel: Implications for I_Ks Channelopathy
The Journal of Membrane Biology, 2011Co-Authors: Yuhong Wang, Kai-ling Hsu, Xulin Xu, Mei Zhang, Min Jiang, Gea-ny TsengAbstract:Cardiac slow delayed rectifier (I_Ks) channel complex consists of KCNQ1 channel and KCNE1 auxiliary subunits. The extracellular juxtamembranous region of KCNE1 is an unstructured loop that contacts multiple KCNQ1 positions in a gating-state-dependent manner. Congenital Arrhythmia-related mutations have been identified in the extracellular S1–S2 linker of KCNQ1. These mutations manifest abnormal phenotypes only when coexpressed with KCNE1, pointing to the importance of proper KCNQ1/KCNE1 interactions here in I_Ks channel function. We investigate the interactions between the KCNE1 loop (positions 36–47) and KCNQ1 S1–S2 linker (positions 140–148) by means of disulfide trapping and voltage clamp techniques. During transitions among the resting-state conformations, KCNE1 positions 36–43 make contacts with KCNQ1 positions 144, 145, and 147 in a parallel fashion. During conformational changes in the activated state, KCNE1 position 40 can make contacts with all three KCNQ1 positions, while the neighboring KCNE1 positions (36, 38, 39, and 41) can make contact with KCNQ1 position 147. Furthermore, KCNQ1 positions 143 and 146 are high-impact positions that cannot tolerate cysteine substitution. To maintain the proper I_Ks channel function, position 143 requires a small side chain with a hydroxyl group, and position 146 requires a negatively charged side chain. These data and the proposed molecular motions provide insights into the mechanisms by which mutations in the extracellular juxtamembranous region of the I_Ks channel impair its function.
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Gating-related molecular motions in the extracellular domain of the IKs channel: implications for IKs channelopathy.
The Journal of membrane biology, 2010Co-Authors: Yuhong Wang, Kai-ling Hsu, Mei Zhang, Min Jiang, Gea-ny TsengAbstract:Cardiac slow delayed rectifier (IKs) channel complex consists of KCNQ1 channel and KCNE1 auxiliary subunits. The extracellular juxtamembranous region of KCNE1 is an unstructured loop that contacts multiple KCNQ1 positions in a gating-state-dependent manner. Congenital Arrhythmia-related mutations have been identified in the extracellular S1–S2 linker of KCNQ1. These mutations manifest abnormal phenotypes only when coexpressed with KCNE1, pointing to the importance of proper KCNQ1/KCNE1 interactions here in IKs channel function. We investigate the interactions between the KCNE1 loop (positions 36–47) and KCNQ1 S1–S2 linker (positions 140–148) by means of disulfide trapping and voltage clamp techniques. During transitions among the resting-state conformations, KCNE1 positions 36–43 make contacts with KCNQ1 positions 144, 145, and 147 in a parallel fashion. During conformational changes in the activated state, KCNE1 position 40 can make contacts with all three KCNQ1 positions, while the neighboring KCNE1 positions (36, 38, 39, and 41) can make contact with KCNQ1 position 147. Furthermore, KCNQ1 positions 143 and 146 are high-impact positions that cannot tolerate cysteine substitution. To maintain the proper IKs channel function, position 143 requires a small side chain with a hydroxyl group, and position 146 requires a negatively charged side chain. These data and the proposed molecular motions provide insights into the mechanisms by which mutations in the extracellular juxtamembranous region of the IKs channel impair its function.
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Differential Molecular Motions of KCNE Subunits in the IKs Channel Complex Detected by Substituted Cysteine-Accessibility Test and Disulfide-Trapping Experiments
Biophysical Journal, 2010Co-Authors: Yuhong Wang, Kai-ling Hsu, Mei Zhang, Min Jiang, Gea-ny TsengAbstract:The IKs channel consists of a pore-forming KCNQ1 channel and auxiliary KCNE subunits: KCNE1 as the major determinant of IKs gating kinetics while KCNE2 as a regulator of IKs current amplitude. Knowledge about the structural basis of KCNQ1 modulation by these different KCNE subunits can help the design of KCNE-specific IKs modulators as antiarrhythmic agents. Recent studies showed that the extracellular-juxtamembranous region of KCNE1 could adopt highly flexible structures and make gating state-dependent contacts with the voltage-sensing domain (VSD) and pore-domain (PD) of KCNQ1. KCNQ1-KCNE1 interactions in this extracellular-juxtamembranous region are critical for the IKs channel function, as evidenced by Congenital Arrhythmia-associated mutations identified in this region. Whether KCNE2 can do the same is unclear. We systematically probe the functional role of the extracellular-juxtamembranous region of KCNE1 (positions 36-47) and KCNE2 (positions 39-50), using cysteine-scanning mutagenesis followed by cysteine-accessibility test and disulfide-trapping experiments. MTSET modification of KCNE1 40C-46C alters the voltage-dependence of IKs activation and, for 44C-46C, reduces the current amplitude. There is a gradient in MTSET modification rates, from fast-reacting (41C-42C) to slow-reacting (44C-46C), with 43C reporting state-dependent accessibility: fast-reacting in open-state & slow-reacting in closed-state. While extensive disulfide-bond partners are found between KCNE1 36C-43C and KCNQ1 144C-147C, no such disulfide-bond partners can be identified between the equivalent KCNE2 positions and KCNQ1 140C-148C. We propose that the KCNE transmembrane helices reside in the junction between VSDs and PD of the KCNQ1 channel, with a similar orientation (with respect to KCNQ1) and position (with respect to membrane bilayer). However, their extracellular-juxtamembranous regions can make differential contacts with KCNQ1, that contribute to their differential effects on the KCNQ1 channel function and provide an opportunity for the design of KCNE-specific IKs modulators.
Peter J Mohler - One of the best experts on this subject based on the ideXlab platform.
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defining the cellular phenotype of ankyrin b syndrome variants human ank2 variants associated with clinical phenotypes display a spectrum of activities in cardiomyocytes
Circulation, 2007Co-Authors: Peter J Mohler, Solena Le Scouarnec, John S Lowe, Lise Caron, Iwona Driskell, Jeanjacques Schott, Kris Norris, Pascale Guicheney, Isabelle Denjoy, Antoine LeenhardtAbstract:Background— Mutations in the ankyrin-B gene (ANK2) cause type 4 long-QT syndrome and have been described in kindreds with other Arrhythmias. The frequency of ANK2 variants in large populations and molecular mechanisms underlying the variability in the clinical phenotypes are not established. More importantly, there is no cellular explanation for the range of severity of cardiac phenotypes associated with specific ANK2 variants. Methods and Results— We performed a comprehensive screen of ANK2 in populations (control, Congenital Arrhythmia, drug-induced long-QT syndrome) of different ethnicities to discover unidentified ANK2 variants. We identified 7 novel nonsynonymous ANK2 variants; 4 displayed abnormal activity in cardiomyocytes. Including the 4 new variants, 9 human ANK2 loss-of-function variants have been identified. However, the clinical phenotypes associated with these variants vary strikingly, from no obvious phenotype to manifest long-QT syndrome and sudden death, suggesting that mutants confer a s...
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Defining the Cellular Phenotype of “Ankyrin-B Syndrome” Variants Human ANK2 Variants Associated With Clinical Phenotypes Display a Spectrum of Activities in Cardiomyocytes
Circulation, 2007Co-Authors: Peter J Mohler, Solena Le Scouarnec, John S Lowe, Lise Caron, Iwona Driskell, Jeanjacques Schott, Kris Norris, Pascale Guicheney, Isabelle Denjoy, Antoine LeenhardtAbstract:Background— Mutations in the ankyrin-B gene (ANK2) cause type 4 long-QT syndrome and have been described in kindreds with other Arrhythmias. The frequency of ANK2 variants in large populations and molecular mechanisms underlying the variability in the clinical phenotypes are not established. More importantly, there is no cellular explanation for the range of severity of cardiac phenotypes associated with specific ANK2 variants. Methods and Results— We performed a comprehensive screen of ANK2 in populations (control, Congenital Arrhythmia, drug-induced long-QT syndrome) of different ethnicities to discover unidentified ANK2 variants. We identified 7 novel nonsynonymous ANK2 variants; 4 displayed abnormal activity in cardiomyocytes. Including the 4 new variants, 9 human ANK2 loss-of-function variants have been identified. However, the clinical phenotypes associated with these variants vary strikingly, from no obvious phenotype to manifest long-QT syndrome and sudden death, suggesting that mutants confer a s...
Min Jiang - One of the best experts on this subject based on the ideXlab platform.
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Gating-Related Molecular Motions in the Extracellular Domain of the I_Ks Channel: Implications for I_Ks Channelopathy
The Journal of Membrane Biology, 2011Co-Authors: Yuhong Wang, Kai-ling Hsu, Xulin Xu, Mei Zhang, Min Jiang, Gea-ny TsengAbstract:Cardiac slow delayed rectifier (I_Ks) channel complex consists of KCNQ1 channel and KCNE1 auxiliary subunits. The extracellular juxtamembranous region of KCNE1 is an unstructured loop that contacts multiple KCNQ1 positions in a gating-state-dependent manner. Congenital Arrhythmia-related mutations have been identified in the extracellular S1–S2 linker of KCNQ1. These mutations manifest abnormal phenotypes only when coexpressed with KCNE1, pointing to the importance of proper KCNQ1/KCNE1 interactions here in I_Ks channel function. We investigate the interactions between the KCNE1 loop (positions 36–47) and KCNQ1 S1–S2 linker (positions 140–148) by means of disulfide trapping and voltage clamp techniques. During transitions among the resting-state conformations, KCNE1 positions 36–43 make contacts with KCNQ1 positions 144, 145, and 147 in a parallel fashion. During conformational changes in the activated state, KCNE1 position 40 can make contacts with all three KCNQ1 positions, while the neighboring KCNE1 positions (36, 38, 39, and 41) can make contact with KCNQ1 position 147. Furthermore, KCNQ1 positions 143 and 146 are high-impact positions that cannot tolerate cysteine substitution. To maintain the proper I_Ks channel function, position 143 requires a small side chain with a hydroxyl group, and position 146 requires a negatively charged side chain. These data and the proposed molecular motions provide insights into the mechanisms by which mutations in the extracellular juxtamembranous region of the I_Ks channel impair its function.
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Gating-related molecular motions in the extracellular domain of the IKs channel: implications for IKs channelopathy.
The Journal of membrane biology, 2010Co-Authors: Yuhong Wang, Kai-ling Hsu, Mei Zhang, Min Jiang, Gea-ny TsengAbstract:Cardiac slow delayed rectifier (IKs) channel complex consists of KCNQ1 channel and KCNE1 auxiliary subunits. The extracellular juxtamembranous region of KCNE1 is an unstructured loop that contacts multiple KCNQ1 positions in a gating-state-dependent manner. Congenital Arrhythmia-related mutations have been identified in the extracellular S1–S2 linker of KCNQ1. These mutations manifest abnormal phenotypes only when coexpressed with KCNE1, pointing to the importance of proper KCNQ1/KCNE1 interactions here in IKs channel function. We investigate the interactions between the KCNE1 loop (positions 36–47) and KCNQ1 S1–S2 linker (positions 140–148) by means of disulfide trapping and voltage clamp techniques. During transitions among the resting-state conformations, KCNE1 positions 36–43 make contacts with KCNQ1 positions 144, 145, and 147 in a parallel fashion. During conformational changes in the activated state, KCNE1 position 40 can make contacts with all three KCNQ1 positions, while the neighboring KCNE1 positions (36, 38, 39, and 41) can make contact with KCNQ1 position 147. Furthermore, KCNQ1 positions 143 and 146 are high-impact positions that cannot tolerate cysteine substitution. To maintain the proper IKs channel function, position 143 requires a small side chain with a hydroxyl group, and position 146 requires a negatively charged side chain. These data and the proposed molecular motions provide insights into the mechanisms by which mutations in the extracellular juxtamembranous region of the IKs channel impair its function.
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Differential Molecular Motions of KCNE Subunits in the IKs Channel Complex Detected by Substituted Cysteine-Accessibility Test and Disulfide-Trapping Experiments
Biophysical Journal, 2010Co-Authors: Yuhong Wang, Kai-ling Hsu, Mei Zhang, Min Jiang, Gea-ny TsengAbstract:The IKs channel consists of a pore-forming KCNQ1 channel and auxiliary KCNE subunits: KCNE1 as the major determinant of IKs gating kinetics while KCNE2 as a regulator of IKs current amplitude. Knowledge about the structural basis of KCNQ1 modulation by these different KCNE subunits can help the design of KCNE-specific IKs modulators as antiarrhythmic agents. Recent studies showed that the extracellular-juxtamembranous region of KCNE1 could adopt highly flexible structures and make gating state-dependent contacts with the voltage-sensing domain (VSD) and pore-domain (PD) of KCNQ1. KCNQ1-KCNE1 interactions in this extracellular-juxtamembranous region are critical for the IKs channel function, as evidenced by Congenital Arrhythmia-associated mutations identified in this region. Whether KCNE2 can do the same is unclear. We systematically probe the functional role of the extracellular-juxtamembranous region of KCNE1 (positions 36-47) and KCNE2 (positions 39-50), using cysteine-scanning mutagenesis followed by cysteine-accessibility test and disulfide-trapping experiments. MTSET modification of KCNE1 40C-46C alters the voltage-dependence of IKs activation and, for 44C-46C, reduces the current amplitude. There is a gradient in MTSET modification rates, from fast-reacting (41C-42C) to slow-reacting (44C-46C), with 43C reporting state-dependent accessibility: fast-reacting in open-state & slow-reacting in closed-state. While extensive disulfide-bond partners are found between KCNE1 36C-43C and KCNQ1 144C-147C, no such disulfide-bond partners can be identified between the equivalent KCNE2 positions and KCNQ1 140C-148C. We propose that the KCNE transmembrane helices reside in the junction between VSDs and PD of the KCNQ1 channel, with a similar orientation (with respect to KCNQ1) and position (with respect to membrane bilayer). However, their extracellular-juxtamembranous regions can make differential contacts with KCNQ1, that contribute to their differential effects on the KCNQ1 channel function and provide an opportunity for the design of KCNE-specific IKs modulators.