The IKr drug response is modulated by KCR1 in transfected cardiac and noncardiac cell lines.
The cardiac potassium channel encoded by the human ether-à-go-go related gene (HERG) is blocked by a diverse array of common therapeutic compounds. Even transient exposure to such agents may provoke the life-threatening cardiac arrhythmia torsades de pointes in some, but not all, individuals. Although the molecular and genetic factors predicting such wide variability in drug response remain unclear, known sequence variations within the coding region of HERG do not explain the adverse drug response in many cases. Although other proteins can modulate HERG function, no studies have identified protein partners capable of limiting the pharmacological sensitivity of HERG. Here we show that KCR1, a protein identified previously in rat cerebellum, is a plasma membrane-associated protein expressed at the RNA level in the human heart and can be immunoprecipitated with HERG. Functionally, KCR1 reduces the sensitivity of HERG to classic proarrhythmic HERG blockers (sotalol, quinidine, dofetilide) in both cardiac and noncardiac cell lines. We propose that KCR1, when coupled to HERG, may limit the sensitivity of HERG to proarrhythmic drug blockade and may be a rational target for modifying the proarrhythmic effects of otherwise clinically useful compounds.
Kupershmidt
Sabina
S
Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, TN 37232-6602, USA. sabina.kupershmidt@vanderbilt.edu
Yang
Iris C-H
IC
Hayashi
Kenshi
K
Wei
Jian
J
Chanthaphaychith
Siprachanh
S
Petersen
Christina I
CI
Johns
Daivid C
DC
George
Alfred L
AL
Roden
Dan M
DM
Balser
Jeffrey R
JR
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D016466:CHO Cells; D027682:Cation Transport Proteins; D002460:Cell Line; D006224:Cricetinae; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D004553:Electric Conductivity; D051638:Ether-A-Go-Go Potassium Channels; D005964:Glucosyltransferases / Q000378:metabolism; D006801:Humans; D015640:Ion Channel Gating; D026901:Membrane Transport Proteins / Q000378:metabolism; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D026902:Potassium Channel Blockers / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D015221:Potassium Channels / Q000235:genetics / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D014162:Transfection
C114599:Alg10 protein, rat; D000889:Anti-Arrhythmia Agents; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; C059983:potassium channel protein I(sk); C518821:ALG10B protein, human; D005964:Glucosyltransferases