Retention in the endoplasmic reticulum as a mechanism of dominant-negativecurrent suppression in human long QT syndrome

Citation
E. Ficker et al., Retention in the endoplasmic reticulum as a mechanism of dominant-negativecurrent suppression in human long QT syndrome, J MOL CEL C, 32(12), 2000, pp. 2327-2337
Citations number
30
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Cardiovascular & Hematology Research
Journal title
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
ISSN journal
0022-2828 → ACNP
Volume
32
Issue
12
Year of publication
2000
Pages
2327 - 2337
Database
ISI
SICI code
0022-2828(200012)32:12<2327:RITERA>2.0.ZU;2-S
Abstract
Mutations in the cardiac potassium channel HERG (KCNH2) cause chromosome 7- linked long QT syndrome (LQT2) characterized by a prolonged QT interval, re current syncope and sudden cardiac death. Most mutations in HERG exhibit "l oss of function" phenotypes with defective channels either inserted into th e plasma membrane or retained in the endoplasmic reticulum. "Loss of functi on" mutations reduce I-Kr, the cardiac delayed rectifier current encoded by HERG, due to haploinsufficiency or suppression of wild-type function by a dominant-negative mechanism. One explanation for dominant-negative current suppression is that mutant subunits render tetrameric channel complexes non -conducting on co-assembly. In the present paper we describe an alternative mechanism for this phenomenon. We show (1) that the dominant-negative HERG mutation A561V is retained in the endoplasmic reticulum and (2) that wild- type channels are tagged for retention in the ER by co-assembly with traffi cking deficient A561V subunits. Thus, in HERG A561V dominant-negative suppr ession of wild-type function is the result of an acquired trafficking defec t. (C) 2000 Academic Press.