Herg Cardiac Potassium Channel - Structure, Function and Long Qt Syndrome

Klappentext Since being identified in 1995 as a major culprit in congenital and acquired forms of long QT syndrome, the fundamental importance of hERG (the human ether-à-go-go-related gene) has been recognized by academic scientists, regulatory authorities dealing with new drug registration and pharmaceutical companies alike. This has coincided with an explosion in the molecular, structural and detection techniques available to researchers studying ion channel structure and function.hERG encodes the pore-forming subunit of the rapid component of the delayed rectifier potassium current in cardiac mycoytes, I_Kr. Physiologically, it is one of several ion channels involved in the normal action potential repolarization in cardiac myocytes. Pharmacologically, it is the target for class III antiarrhythmic agents, e.g. quinidine, amiodarone and dofetilide. Toxicologically, it is considered to demonstrate promiscuous binding to a wide range of structurally diverse compounds leading to prolongation of the QT interval. This drug-induced QT interval prolongation, leading to risk of ventricular tachyarrhythmia, Torsade de Pointes and mortality, has precipitated the withdrawal of medicines from the market, particularly amongst certain therapeutic classes including antihistamines, gastrointestinal prokinetics, antipsychotics and antibiotics.This book draws together contributions from basic, pharmaceutical and clinical sciences and regulatory authority perspectives aimed at a better understanding of the structure and function of hERG, the molecular basis for compound binding and preferred preclinical test systems. Topics include hERG channel gating, regulation of functional expression, pharmacological properties of hERG/I_Kr channels, drug-induced long QT syndrome and preclinical evaluation and regulatory recommendations for assessing QT prolongation risks. It is hoped that a better understanding of the role of the hERG channel in drug-induced cardiac arrhythmias will lead to the development of new and safer medicines. Zusammenfassung This book draws together contributions from basic, pharmaceutical and clinical sciences aimed at a better understanding of the structure and function of hERG and the molecular basis for compound binding.It features regulatory authority perspectives on preferred preclinical test systems and includes topics on hERG channel gating, regulation of functional expression, pharmacological properties of hERG/IKr channels, drug-induced long QT syndrome and preclinical evaluation and regulatory recommendations for assessing QT prolongation risks.Better understanding of the role of the hERG channel in drug-induced cardiac arrhythmias should ultimately lead to the development of important, new and safer medicines. Inhaltsverzeichnis Chair's introduction (Michael Sanguinetti).Gating and assembly of heteromeric hERG1a/1b channels underlying I_Kr in the heart (Gail A. Robertson, Eugenia M. C. Jones and Jinling Wang).Structure-function studies of outer mouth and voltage sensor domain of hERG (Gea-Ny Tseng and H. Robert Guy).Voltage sensor movement in the hERG K+ channel (David R. Piper,Michael C. Sanguinetti and Martin Tristani-Firouzi).hERG channel trafficking (Eckhard Ficker, Adrienne Dennis,Yuri Kuryshev, Barbara A.Wible and Arthur M. Brown).Dynamic control of hERG/_IKr_r by PKA-mediated interactions with 14-3-3 (Anna Kagan and Thomas V. McDonald).Does hERG coassemble with a ß subunit? Evidence for roles of MinK and MiRP1 (Arun Anantharam and Geoffrey W. Abbott).hERG block, QT liability and sudden cardiac death (Arthur M. Brown).Structural determinants for high affinity block of hERG potassium channels ( John Mitcheson, Matthew Perry, Phillip Stansfeld,Mike Sanguinetti,Harry Witchel and Jules Hancox).Physicochemical basis for binding and voltage-dependent block of hERG channels by structurally diverse drugs (Michael C. Sanguinetti, Jun Chen, David Fernandez, Kaichir...

List of contents

Chair's introduction (Michael Sanguinetti).

Gating and assembly of heteromeric hERG1a/1b channels underlying I_Kr in the heart (Gail A. Robertson, Eugenia M. C. Jones and Jinling Wang).

Structure-function studies of outer mouth and voltage sensor domain of hERG (Gea-Ny Tseng and H. Robert Guy).

Voltage sensor movement in the hERG K+ channel (David R. Piper,Michael C. Sanguinetti and Martin Tristani-Firouzi).

hERG channel trafficking (Eckhard Ficker, Adrienne Dennis,Yuri Kuryshev, Barbara A.Wible and Arthur M. Brown).

Dynamic control of hERG/_IKr_r by PKA-mediated interactions with 14-3-3 (Anna Kagan and Thomas V. McDonald).

Does hERG coassemble with a ß subunit? Evidence for roles of MinK and MiRP1 (Arun Anantharam and Geoffrey W. Abbott).

hERG block, QT liability and sudden cardiac death (Arthur M. Brown).

Structural determinants for high affinity block of hERG potassium channels ( John Mitcheson, Matthew Perry, Phillip Stansfeld,Mike Sanguinetti,Harry Witchel and Jules Hancox).

Physicochemical basis for binding and voltage-dependent block of hERG channels by structurally diverse drugs (Michael C. Sanguinetti, Jun Chen, David Fernandez, Kaichiro Kamiya,John Mitcheson and José A. Sanchez-Chapula).

In silico - modelling pharmacophores and hERG channel models (Maurizio Recanatini, Andrea Cavalli and MatteoMasetti).

The long QT syndrome: a clinical counterpart of HERG mutations (Peter J. Schwartz).

Cellular mechanisms of Torsade de Pointes (Steven Poelzing and David S. Rosenbaum).

Expression and role of HERG channels in cancer cells (Annarosa Arcangeli).

TRIad: foundation for proarrhythmia (triangulation, reverse use dependence and instability) (Luc M. Hondeghem).

Drug-induced QT interval prolongation: regulatory guidance and perspectives on hERG channel studies (Rashmi R. Shah).

Closing remarks (Michael Sanguinetti).

Index of contributors.

Subject index.

Report

" a useful reference for current literature and developments on the cardiac hERG potassium channel. No other books are currently available on the subject." ( Doody s Health Services )

Product details

• Authors: Derek J. Goode Chadwick, Novartis Foundation, Novartis, NOVARTIS FOUNDATION, Novartis Foundation Symposium
• Publisher: Wiley, John and Sons Ltd
• Languages: English
• Product format: Hardback
• Released: 11.02.2005
• EAN: 9780470021408
• ISBN: 978-0-470-02140-8
• No. of pages: 308
• Series: Novartis Foundation Symposium; Novartis Foundation Symposia; Novartis Foundation Symposia; Novartis Foundation Symposium
• Subject: Natural sciences, medicine, IT, technology > Biology > Microbiology