title: hERG subunit composition determines differential drug sensitivity.
abstract: OBJECTIVE
  The majority of human ether-a-go-go-related gene (hERG) screens aiming to minimize the risk of drug-induced long QT syndrome have been conducted using heterologous systems expressing the hERG 1a subunit, although both hERG 1a and 1b subunits contribute to the K+ channels producing the repolarizing current I(Kr) . We tested a range of compounds selected for their diversity to determine whether hERG 1a and 1a/1b channels exhibit different sensitivities that may influence safety margins or contribute to a stratified risk analysis.
  
  
  METHODS
  We used the IonWorks™ plate-based electrophysiology device to compare sensitivity of hERG 1a and 1a/1b channels stably expressed in HEK293 cells to 50 compounds previously shown to target hERG channels. Potency was determined as IC₅₀ values (µM) obtained from non-cumulative, eight-point concentration-effect curves of normalized data, fitted to the Hill equation. To minimize possible sources of variability, compound potency was assessed using test plates arranged in alternating columns of cells expressing hERG 1a and 1a/1b.
  
  
  RESULTS
  Although the potency of most compounds was similar for the two targets, some surprising differences were observed. Fluoxetine (Prozac) was more potent at blocking hERG 1a/1b than 1a channels, yielding a corresponding reduction in the safety margin. In contrast, E-4031 was a more potent blocker of hERG 1a compared with 1a/1b channels, as previously reported, as was dofetilide, another high-affinity blocker.
  
  
  CONCLUSIONS
  The current assays may underestimate the risk of some drugs to cause torsades de pointes arrhythmia, and overestimate the risk of others.
authors: Safety Pharmacology, Safety Assessment UK, AstraZeneca R&D Alderley Park, Macclesfield, UK. najah.abigerges@astrazeneca.com
authors: N
authors: N
authors: Abi-Gerges
authors: H
authors: H
authors: Holkham
authors: E M C
authors: EM
authors: Jones
authors: C E
authors: CE
authors: Pollard
authors: J-P
authors: JP
authors: Valentin
authors: G A
authors: GA
authors: Robertson
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000235:genetics; D002461:Cell Line, Transformed; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics; D005473:Fluoxetine / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008133:Long QT Syndrome / Q000139:chemically induced / Q000235:genetics; D010880:Piperidines / Q000494:pharmacology; D021122:Protein Subunits; D011725:Pyridines / Q000494:pharmacology; D012680:Sensitivity and Specificity; D016171:Torsades de Pointes / Q000139:chemically induced / Q000235:genetics
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human; C092509:KCNH6 protein, human; D010880:Piperidines; D021122:Protein Subunits; D011725:Pyridines; D005473:Fluoxetine; C063968:E 4031