scholarly journals Allosteric mechanism for KCNE1 modulation of KCNQ1 potassium channel activation

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Georg Kuenze ◽  
Carlos G Vanoye ◽  
Reshma R Desai ◽  
Sneha Adusumilli ◽  
Kathryn R Brewer ◽  
...  
Keyword(s):  
Potassium Channel ◽  
Binding Mode ◽  
Channel Structure ◽  
Delayed Rectifier ◽  
Delayed Rectifier Current ◽  
Cardiac Action ◽  
Allosteric Mechanism ◽  
Channel Gate ◽  
Electrophysiological Studies ◽  
Functional Modulation

The function of the voltage-gated KCNQ1 potassium channel is regulated by co-assembly with KCNE auxiliary subunits. KCNQ1-KCNE1 channels generate the slow delayed rectifier current, IKs, which contributes to the repolarization phase of the cardiac action potential. A three amino acid motif (F57-T58-L59, FTL) in KCNE1 is essential for slow activation of KCNQ1-KCNE1 channels. However, how this motif interacts with KCNQ1 to control its function is unknown. Combining computational modeling with electrophysiological studies, we developed structural models of the KCNQ1-KCNE1 complex that suggest how KCNE1 controls KCNQ1 activation. The FTL motif binds at a cleft between the voltage-sensing and pore domains and appears to affect the channel gate by an allosteric mechanism. Comparison with the KCNQ1-KCNE3 channel structure suggests a common transmembrane-binding mode for different KCNEs and illuminates how specific differences in the interaction of their triplet motifs determine the profound differences in KCNQ1 functional modulation by KCNE1 versus KCNE3.

scholarly journals Structure and physiological function of the human KCNQ1 channel voltage sensor intermediate state

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Keenan C Taylor ◽  
Po Wei Kang ◽  
Panpan Hou ◽  
Nien-Du Yang ◽  
Georg Kuenze ◽  
...  
Keyword(s):  
Potassium Channel ◽  
Intermediate State ◽  
Three Dimensional ◽  
Voltage Sensor ◽  
Dimensional Structure ◽  
Delayed Rectifier ◽  
Voltage Gated ◽  
Delayed Rectifier Current ◽  
Activated State ◽  
Voltage Gated Ion Channels

Voltage-gated ion channels feature voltage sensor domains (VSDs) that exist in three distinct conformations during activation: resting, intermediate, and activated. Experimental determination of the structure of a potassium channel VSD in the intermediate state has previously proven elusive. Here, we report and validate the experimental three-dimensional structure of the human KCNQ1 voltage-gated potassium channel VSD in the intermediate state. We also used mutagenesis and electrophysiology in Xenopus laevisoocytes to functionally map the determinants of S4 helix motion during voltage-dependent transition from the intermediate to the activated state. Finally, the physiological relevance of the intermediate state KCNQ1 conductance is demonstrated using voltage-clamp fluorometry. This work illuminates the structure of the VSD intermediate state and demonstrates that intermediate state conductivity contributes to the unusual versatility of KCNQ1, which can function either as the slow delayed rectifier current (IKs) of the cardiac action potential or as a constitutively active epithelial leak current.

scholarly journals Molecular Pathophysiology of Congenital Long QT Syndrome

2017 ◽  
Vol 97 (1) ◽  
pp. 89-134 ◽  
Author(s):  
M. S. Bohnen ◽  
G. Peng ◽  
S. H. Robey ◽  
C. Terrenoire ◽  
V. Iyer ◽  
...  
Keyword(s):  
Ion Channel ◽  
Long Qt Syndrome ◽  
Clinical Management ◽  
Cardiac Electrophysiology ◽  
Channel Structure ◽  
Delayed Rectifier ◽  
Long Qt ◽  
Delayed Rectifier Current ◽  
Qt Syndrome ◽  
Congenital Long Qt Syndrome

Ion channels represent the molecular entities that give rise to the cardiac action potential, the fundamental cellular electrical event in the heart. The concerted function of these channels leads to normal cyclical excitation and resultant contraction of cardiac muscle. Research into cardiac ion channel regulation and mutations that underlie disease pathogenesis has greatly enhanced our knowledge of the causes and clinical management of cardiac arrhythmia. Here we review the molecular determinants, pathogenesis, and pharmacology of congenital Long QT Syndrome. We examine mechanisms of dysfunction associated with three critical cardiac currents that comprise the majority of congenital Long QT Syndrome cases: 1) IKs, the slow delayed rectifier current; 2) IKr, the rapid delayed rectifier current; and 3) INa, the voltage-dependent sodium current. Less common subtypes of congenital Long QT Syndrome affect other cardiac ionic currents that contribute to the dynamic nature of cardiac electrophysiology. Through the study of mutations that cause congenital Long QT Syndrome, the scientific community has advanced understanding of ion channel structure-function relationships, physiology, and pharmacological response to clinically employed and experimental pharmacological agents. Our understanding of congenital Long QT Syndrome continues to evolve rapidly and with great benefits: genotype-driven clinical management of the disease has improved patient care as precision medicine becomes even more a reality.

scholarly journals Modulation of the Cardiac Myocyte Action Potential by the Magnesium-Sensitive TRPM6 and TRPM7-like Current

2021 ◽  
Vol 22 (16) ◽  
pp. 8744
Author(s):  
Asfree Gwanyanya ◽  
Inga Andriulė ◽  
Bogdan M. Istrate ◽  
Farjana Easmin ◽  
Kanigula Mubagwa ◽  
...  
Keyword(s):  
Patch Clamp ◽  
Action Potential ◽  
Voltage Clamp ◽  
Divalent Cation ◽  
Cardiac Myocyte ◽  
Cardiac Action Potential ◽  
Delayed Rectifier ◽  
Delayed Rectifier Current ◽  
Cardiac Action ◽  
In Cells

The cardiac Mg2+-sensitive, TRPM6, and TRPM7-like channels remain undefined, especially with the uncertainty regarding TRPM6 expression in cardiomyocytes. Additionally, their contribution to the cardiac action potential (AP) profile is unclear. Immunofluorescence assays showed the expression of the TRPM6 and TRPM7 proteins in isolated pig atrial and ventricular cardiomyocytes, of which the expression was modulated by incubation in extracellular divalent cation-free conditions. In patch clamp studies of cells dialyzed with solutions containing zero intracellular Mg2+ concentration ([Mg2+]i) to activate the Mg2+-sensitive channels, raising extracellular [Mg2+] ([Mg2+]o) from the 0.9-mM baseline to 7.2 mM prolonged the AP duration (APD). In contrast, no such effect was observed in cells dialyzed with physiological [Mg2+]i. Under voltage clamp, in cells dialyzed with zero [Mg2+]i, depolarizing ramps induced an outward-rectifying current, which was suppressed by raising [Mg2+]o and was absent in cells dialyzed with physiological [Mg2+]i. In cells dialyzed with physiological [Mg2+]i, raising [Mg2+]o decreased the L-type Ca2+ current and the total delayed-rectifier current but had no effect on the APD. These results suggest a co-expression of the TRPM6 and TRPM7 proteins in cardiomyocytes, which are therefore the molecular candidates for the native cardiac Mg2+-sensitive channels, and also suggest that the cardiac Mg2+-sensitive current shortens the APD, with potential implications in arrhythmogenesis.

Expression and coassociation of ERG1, KCNQ1, and KCNE1 potassium channel proteins in horse heart

2002 ◽  
Vol 283 (1) ◽  
pp. H126-H138 ◽  
Author(s):  
Melissa R. Finley ◽  
Yan Li ◽  
Fei Hua ◽  
James Lillich ◽  
Kathy E. Mitchell ◽  
...  
Keyword(s):  
Cardiac Arrhythmias ◽  
Molecular Basis ◽  
Cardiac Tissue ◽  
Delayed Rectifier ◽  
Related Gene ◽  
Rt Pcr ◽  
Delayed Rectifier Current ◽  
Cardiac Action ◽  
Qt Syndrome ◽  
Α Subunits

In dogs and in humans, potassium channels formed by ether-a-go-go-related gene 1 protein ERG1 (KCNH2) and KCNQ1 α-subunits, in association with KCNE β-subunits, play a role in normal repolarization and may contribute to abnormal repolarization associated with long QT syndrome (LQTS). The molecular basis of repolarization in horse heart is unknown, although horses exhibit common cardiac arrhythmias and may receive drugs that induce LQTS. In horse heart, we have used immunoblotting and immunostaining to demonstrate the expression of ERG1, KCNQ1, KCNE1, and KCNE3 proteins and RT-PCR to detect KCNE2 message. Peptide N-glycosidase F-sensitive forms of horse ERG1 (145 kDa) and KCNQ1 (75 kDa) were detected. Both ERG1 and KCNQ1 coimmunoprecipitated with KCNE1. Cardiac action potential duration was prolonged by antagonists of either ERG1 (MK-499, cisapride) or KCNQ1/KCNE1 (chromanol 293B). Patch-clamp analysis confirmed the presence of a slow delayed rectifier current. These data suggest that repolarizing currents in horses are similar to those of other species, and that horses are therefore at risk for acquired LQTS. The data also provide unique evidence for coassociation between ERG1 and KCNE1 in cardiac tissue.

How to Fluorescently Label the Potassium Channel: A Case in hERG

2020 ◽  
Vol 27 (18) ◽  
pp. 3046-3054
Author(s):  
Xiaomeng Zhang ◽  
Beilei Wang ◽  
Zhenzhen Liu ◽  
Yubin Zhou ◽  
Lupei Du
Keyword(s):  
Potassium Channel ◽  
Herg Channel ◽  
Pore Channel ◽  
Design Rationale ◽  
Related Gene ◽  
Open Conformation ◽  
Cardiac Action ◽  
Qt Syndrome ◽  
Herg Channels ◽  
Action Potential Repolarization

hERG (Human ether-a-go-go-related gene) potassium channel, which plays an essential role in cardiac action potential repolarization, is responsible for inherited and druginduced long QT syndrome. Recently, the Cryo-EM structure capturing the open conformation of hERG channel was determined, thus pushing the study on hERG channel at 3.8 Å resolution. This report focuses primarily on summarizing the design rationale and application of several fluorescent probes that target hERG channels, which enables dynamic and real-time monitoring of potassium pore channel affinity to further advance the understanding of the channels.

scholarly journals Canine Myocytes Represent a Good Model for Human Ventricular Cells Regarding Their Electrophysiological Properties

2021 ◽  
Vol 14 (8) ◽  
pp. 748
Author(s):  
Péter P. Nánási ◽  
Balázs Horváth ◽  
Fábián Tar ◽  
János Almássy ◽  
Norbert Szentandrássy ◽  
...  
Keyword(s):  
Action Potential ◽  
Time Course ◽  
Laboratory Animals ◽  
Delayed Rectifier ◽  
Ion Currents ◽  
Human Cardiomyocytes ◽  
Ventricular Cells ◽  
Repolarization Reserve ◽  
Electrophysiological Studies ◽  
K Current

Due to the limited availability of healthy human ventricular tissues, the most suitable animal model has to be applied for electrophysiological and pharmacological studies. This can be best identified by studying the properties of ion currents shaping the action potential in the frequently used laboratory animals, such as dogs, rabbits, guinea pigs, or rats, and comparing them to those of human cardiomyocytes. The authors of this article with the experience of three decades of electrophysiological studies, performed in mammalian and human ventricular tissues and isolated cardiomyocytes, summarize their results obtained regarding the major canine and human cardiac ion currents. Accordingly, L-type Ca2+ current (ICa), late Na+ current (INa-late), rapid and slow components of the delayed rectifier K+ current (IKr and IKs, respectively), inward rectifier K+ current (IK1), transient outward K+ current (Ito1), and Na+/Ca2+ exchange current (INCX) were characterized and compared. Importantly, many of these measurements were performed using the action potential voltage clamp technique allowing for visualization of the actual current profiles flowing during the ventricular action potential. Densities and shapes of these ion currents, as well as the action potential configuration, were similar in human and canine ventricular cells, except for the density of IK1 and the recovery kinetics of Ito. IK1 displayed a largely four-fold larger density in canine than human myocytes, and Ito recovery from inactivation displayed a somewhat different time course in the two species. On the basis of these results, it is concluded that canine ventricular cells represent a reasonably good model for human myocytes for electrophysiological studies, however, it must be borne in mind that due to their stronger IK1, the repolarization reserve is more pronounced in canine cells, and moderate differences in the frequency-dependent repolarization patterns can also be anticipated.

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