N-Glycosylation-dependent block is a novel mechanism for drug-induced cardiac arrhythmia.
Voltage-gated potassium channels formed with the cardiac subunit HERG and a polymorphic variant of MinK-related peptide 1 (MiRP1) exhibit increased susceptibility to the antibiotic sulfamethoxazole (SMX) compared with channels formed with wild-type (WT) subunits. Here the molecular bases for SMX high-affinity block are investigated. The polymorphism causes a benign T to A amino acid mutation at position 8 (T8A) that destroys an N-glycosylation site of MiRP1. In vitro disruption of glycosylation by mutagenesis or in vivo by treatment with neuraminidase is associated with increased susceptibility to SMX and to other elementary agents such as divalent cations. Defective glycosylation does not affect the ability of T8A to form stable complexes with HERG, but rather it increases drug susceptibility through structural modifications in the channel complex. We conclude that N-glycosylation may play a key role in the etiology of life-threatening arrhythmia.
Park
Ki-Ho
KH
University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Department of Physiology and Biophysics, Piscataway, NJ 08854, USA.
Kwok
Suk-Mei
SM
Sharon
Chetna
C
Baerga
Rebecca
R
Berga
Rebecca
R
Sesti
Federico
F
D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D027682:Cation Transport Proteins; D004553:Electric Conductivity; D051638:Ether-A-Go-Go Potassium Channels; D006031:Glycosylation; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D013420:Sulfamethoxazole / Q000494:pharmacology*
D027682:Cation Transport Proteins; D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; C059983:potassium channel protein I(sk); D013420:Sulfamethoxazole