title: Pharmacological rescue of human K(+) channel long-QT2 mutations: human ether-a-go-go-related gene rescue without block.
abstract: BACKGROUND
  Defective protein trafficking is a consequence of gene mutations. Human long-QT (LQT) syndrome results from mutations in several genes, including the human ether-a-go-go-related gene (HERG), which encodes a delayed rectifier K(+) current. Trafficking-defective mutant HERG protein is a mechanism for reduced delayed rectifier K(+) current in LQT2, and high-affinity HERG channel-blocking drugs can result in pharmacological rescue. Methods and Results- We postulated that drug molecules modified to remove high-affinity HERG block may still stabilize mutant proteins in a conformation required for rescue. We tested terfenadine carboxylate (fexofenadine) and terfenadine, structurally similar drugs with markedly different affinities for HERG block, for rescue of trafficking-defective LQT2 mutations. Terfenadine rescued the N470D mutation but blocked the channels. In contrast, fexofenadine rescued N470D with a half-maximal rescue concentration of 177 nmol/L, which is approximately 350-fold lower than the half-maximal channel block concentration. The G601S mutation was also rescued without channel block.
  
  
  CONCLUSIONS
  Pharmacological rescue can occur without channel block. This could represent a new antiarrhythmic paradigm in the treatment of some trafficking-defective LQT2 mutations.
authors.affiliation: Department of Medicine, University of Wisconsin, Madison, USA.
authors.forename: Sridharan
authors.initials: S
authors.lastname: Rajamani
authors.forename: Corey L
authors.initials: CL
authors.lastname: Anderson
authors.forename: Blake D
authors.initials: BD
authors.lastname: Anson
authors.forename: Craig T
authors.initials: CT
authors.lastname: January
mesh_terms: D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D004553:Electric Conductivity; D051638:Ether-A-Go-Go Potassium Channels; D006801:Humans; D007700:Kinetics; D008133:Long QT Syndrome / Q000235:genetics; D008564:Membrane Potentials; D009154:Mutation; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000235:genetics* / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D016593:Terfenadine / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D000889:Anti-Arrhythmia Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D016593:Terfenadine; C093230:fexofenadine