The hERG Cardiac Potassium Channel-NOVARTIS基础研讨会

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-&-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 myocytes, /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 anti-arrhythmic 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//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.

Symposium on The hERG cardiac potassium channel: structure, function and longQTsyndrome, held at the Novartis Foundation, London, 4-6 May 2004
Editors: Derek J. Chadwick and Jamie Goode
This symposium h basedon aproposalmade by John Mitcheson, Martin Gosling and Paul Nicklin
Michael C. Sanguinetti Chair's introduction
Gail A. Robertson, Eugenia M. C. Jones andJinlingWang Gating and assembly of heteromeric hERGla/lb channels underlying 1Kr in the heart
Discussion
Gea-NyTseng and H. Robert Guy Structure function studies of the outer mouth and voltage sensor domain of bERG
Discussion
General discussion Ⅰ
David R. Piper, Michael C. Sanguinetti and MartinTristani-Firouzi Voltage sensor movement in the bERG K+ channel
Discussion
Eckhard Ficker, Adrienne Dennis,Yuri Kuryshev, Barbara A.Wible and Arthur M. Brown hERG channel trafficking
Discussion
Anna Kagan and ThomasV. McDonald Dynamic control of hERG/IKr by PKA-mediated interactions with 14-3-3
Discussion
General discussion Ⅱ
Arun Anantharam and Geoffrey w. Abbott Does hERG coassemble with a B subunit? Evidence for roles of MinK and MiRP1
Discussion
Arthur M. Brown hERG block, QT liability and sudden cardiac death
Discussion
John Mitcheson, Matthew Perry, Phillip Stansfeld, Michael Sanguinetti, Harry Witchel and Jules Hancox Structural determinants for high affinity block
of hERG potassium channels
Discussion
General discussion Ⅲ
Michael C. Sanguinetti, Jun Chen, David Fernandez, Kaichiro Kamiya,
John Mitcheson andJose A. Sanchez-Chapula Physicochemical basis for binding and voltage dependent block of hERG channels by structurally diverse drugs
Discussion
Maurizio Recanatini, Andrea Cavalli and Matteo Masetti Insilico modelling pharmacophores and hERG channel models
Discussion
PeterJ. Schwartz The long QTsyndrome: a clinical counterpart of HERG mutations
Discussion
Steven Poelzing and David S. Rosenbaum Cellular mechanisms of Torsade de
Pointes
Discussion
Annarosa Arcangeli Expression and role ofhERG channels in cancer cells
Discussion
Luc M. Hondeghem TRiad: foundation for proarrhythmia (triangulation, reverse use dependence and instability)
Discussion
Rashmi R. Shah Drug-induced QTinterval prolongation: regulatory guidance and perspectives on hERG channel studies
Discussion
Michael C. Sanguinetti Closing remarks
Index of contributors
Subject index