A mechanism for the proarrhythmic effects of cisapride (Propulsid): high affinity blockade of the human cardiac potassium channel HERG

Rampe, David; Roy, Mary-Louise; Dennis, Adrienne T.; Brown, Arthur M.

doi:10.1016/s0014-5793(97)01249-0

Cited by 273 publications

(155 citation statements)

References 20 publications

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“…Cisapride blocked HERG currents with an IC 50 of 6 -7 nM (24,25), and quinidine blocked with an IC 50 of about 1 M (26, 27). We tested whether all of these drugs restored HERG G601S trafficking in a concentration-dependent manner and whether the difference in interaction with the methanesulfonanilide binding site was reflected in their ability to rescue HERG G601S.…”

Section: Restoration Of Herg G601s Trafficking By Incubation Withmentioning

confidence: 99%

The Binding Site for Channel Blockers That Rescue Misprocessed Human Long QT Syndrome Type 2 ether-a-gogo-related Gene (HERG) Mutations

Ficker

Obejero‐Paz

Zhao³

et al. 2002

Journal of Biological Chemistry

163

164

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Mutations in the human ether-a-gogo-related gene (HERG) K؉ channel gene cause chromosome 7-linked long QT syndrome type 2 (LQT2), which is characterized by a prolonged QT interval in the electrocardiogram and an increased susceptibility to life-threatening cardiac arrhythmias. LQT2 mutations produce loss-of-function phenotypes and reduce I Kr currents either by the heteromeric assembly of non-or malfunctioning channel subunits with wild type subunits at the cell surface or by retention of misprocessed mutant HERG channels in the endoplasmic reticulum. Misprocessed mutations often encode for channel proteins that are functional upon incorporation into the plasma membrane. As a result the pharmacological correction of folding defects and restoration of protein function are of considerable interest. Here we report that the trafficking-deficient pore mutation HERG G601S was rescued by a series of HERG channel blockers that increased cell surface expression. Rescue by these pharmacological chaperones varied directly with their blocking potency. We used structure-activity relationships and site-directed mutagenesis to define the binding site of the pharmacological chaperones. We found that binding occurred in the inner cavity and correlated with hydrophobicity and cationic charge. Rescue was domain-restricted because the trafficking of two misprocessed mutations in the C terminus, HERG F805C and HERG R823W, was not restored by channel blockers. Our findings represent a first step toward the design of pharmacological chaperones that will rescue HERG K ؉ channels without block.

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Section: Restoration Of Herg G601s Trafficking By Incubation Withmentioning

confidence: 99%

The Binding Site for Channel Blockers That Rescue Misprocessed Human Long QT Syndrome Type 2 ether-a-gogo-related Gene (HERG) Mutations

Ficker

Obejero‐Paz

Zhao³

et al. 2002

Journal of Biological Chemistry

163

164

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“…There have been reports of fatal cardiac dysrhythmias associated with the combination of cisapride and several agents that are metabolized by the cytochrome P-450 system (particularly antifungal agents and some antimicrobials) (81,82). The widespread use of this medication throughout the world suggests that these important side effects must be relatively rare.…”

Section: The Available Promotility Agents (Cisapride and Metoclopramimentioning

confidence: 99%

Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease

DeVault¹

1999

The American Journal of Gastroenterology

143

178

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PREAMBLEGuidelines for the diagnosis and treatment of gastroesophageal reflux disease (GERD) were published by the American College of Gastroenterology in 1995 (1). These and other guidelines undergo periodic review. Significant advances have been made in the area of GERD over the past several years, leading us to review and revise our previous guidelines statements. These advances have included an increase in our comfort with the chronic use of proton pump inhibitors and an increased acceptance of laparoscopic antireflux surgery, among other factors. These and the original guidelines are intended to apply to all physicians who address GERD and are intended to indicate the preferable, but not only acceptable, approach. Physicians must always choose the course best suited to the individual patient and the variables that exist at the moment of the decision. These guidelines are intended to apply to adult patients with the symptoms, tissue damage, or both that result from the reflux of gastric contents into the esophagus. For the purpose of these guidelines GERD is defined as chronic symptoms or mucosal damage produced by the abnormal reflux of gastric contents into the esophagus.Both these and the original guidelines were developed under the auspices of the American College of Gastroenterology and its Practice Parameters Committee, and approved by the Board of Trustees. The world literature was reviewed extensively for the original guidelines and was once again reviewed using the National Library of Medicine database. All appropriate studies were reviewed and any additional studies found in the reference list of these papers were obtained and reviewed. Evidence was evaluated along a hierarchy, with randomized controlled trials given the greatest weight. Abstracts presented at national and international meetings were only used when unique data from ongoing trials were presented. When scientific data were lacking, recommendations were based on expert consensus. During preparation, the guidelines were reviewed

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“…8 Reduction of I Kr current by mutation of the hERG gene or by drug blockade can cause congenital and acquired LQTS, respectively, 2,3 and unfortunately, acquired LQTS is not an uncommon side effect of a number of commonly used over-the-counter and prescription medications. [9][10][11][12] The susceptibility of the hERG channel to block by so many drugs has led to intense scrutiny of new drugs by regulatory agencies. This in turn has intensified the interest of pharmaceutical companies in high-throughput screening methods to detect, early in the drug development process, compounds that block the hERG channel.…”

Section: Introductionmentioning

confidence: 99%

Rb+ Flux through hERG Channels Affects the Potency of Channel Blocking Drugs: Correlation with Data Obtained Using a High-Throughput Rb+ Efflux Assay

Rezazadeh¹,

Hesketh²,

Fedida³

2004

SLAS Discovery

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The nonradioactive Rb+ efflux assay has become a reliable and efficient high-throughput hERG screening method, but it is limited by its low sensitivity for potent hERG blockers. Using the patch clamp technique, the authors found that the low sensitivity is due in part to the use of Rb+ as the permeating cation in the assay. The affinities of the drugs measured by patch clamp technique in the presence of Rb+ were 3- to 10-fold lower than when measured by the same method in the presence of K+ ions. The apparent affinity of the drugs decreased even further when monitored bytheRb+ efflux assay. It was also observed that Rb+ had minimal effects on the activation properties of channels while there was a significant change in the half-inactivation potential. This voltage shift reduces hERG channel inactivation at efflux assay potentials, and will reduce the affinity of hERG-blocking drugs that bind to inactivated states of the channel. In combination with the effects of elevated extracellular ion concentrations, it is likely that Rb+ modulation of hERG channel inactivation is largely responsible for the reduced drug potencies observed in the Rb+ efflux assay.

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A mechanism for the proarrhythmic effects of cisapride (Propulsid): high affinity blockade of the human cardiac potassium channel HERG

Cited by 273 publications

References 20 publications

The Binding Site for Channel Blockers That Rescue Misprocessed Human Long QT Syndrome Type 2 ether-a-gogo-related Gene (HERG) Mutations

The Binding Site for Channel Blockers That Rescue Misprocessed Human Long QT Syndrome Type 2 ether-a-gogo-related Gene (HERG) Mutations

Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease

Rb+ Flux through hERG Channels Affects the Potency of Channel Blocking Drugs: Correlation with Data Obtained Using a High-Throughput Rb+ Efflux Assay

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