PMID- 10409658
OWN - NLM
STAT- MEDLINE
DCOM- 19990826
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 274
IP  - 30
DP  - 1999 Jul 23
TI  - Long QT syndrome-associated mutations in the S4-S5 linker of KvLQT1 potassium
      channels modify gating and interaction with minK subunits.
PG  - 21063-70
AB  - Long QT syndrome is an inherited disorder of cardiac repolarization caused by
      mutations in cardiac ion channel genes, including KVLQT1. In this study, the
      functional consequences of three long QT-associated missense mutations in KvLQT1 
      (R243C, W248R, E261K) were characterized using the Xenopus oocyte heterologous
      expression system and two-microelectrode voltage clamp techniques. These
      mutations are located in or near the intracellular linker between the S4 and S5
      transmembrane domains, a region implicated in activation gating of potassium
      channels. The E261K mutation caused loss of function and did not interact with
      wild-type KvLQT1 subunits. R243C or W248R KvLQT1 subunits formed functional
      channels, but compared with wild-type KvLQT1 current, the rate of activation was 
      slower, and the voltage dependence of activation and inactivation was shifted to 
      more positive potentials. Co expression of minK and KvLQT1 channel subunits
      induces a slow delayed rectifier K(+) current, I(Ks), characterized by slow
      activation and a markedly increased magnitude compared with current induced by
      KvLQT1 subunits alone. Coexpression of minK with R243C or W248R KvLQT1 subunits
      suppressed current, suggesting that coassembly of mutant subunits with minK
      prevented normal channel gating. The decrease in I(Ks) caused by loss of function
      or altered gating properties explains the prolonged QT interval and increased
      risk of arrhythmia and sudden death associated with these mutations in KVLQT1.
FAU - Franqueza, L
AU  - Franqueza L
AD  - Department of Medicine, Division of Cardiology, University of Utah, Salt Lake
      City, Utah 84112, USA.
FAU - Lin, M
AU  - Lin M
FAU - Shen, J
AU  - Shen J
FAU - Splawski, I
AU  - Splawski I
FAU - Keating, M T
AU  - Keating MT
FAU - Sanguinetti, M C
AU  - Sanguinetti MC
LA  - eng
GR  - HL52338/HL/NHLBI NIH HHS/United States
GR  - HL55236/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (KCNQ Potassium Channels)
RN  - 0 (KCNQ1 Potassium Channel)
RN  - 0 (KCNQ1 protein, human)
RN  - 0 (Potassium Channels)
RN  - 0 (Potassium Channels, Voltage-Gated)
SB  - IM
EIN - J Biol Chem 1999 Aug 27;274(35):25188
MH  - Animals
MH  - Electrophysiology
MH  - Gene Expression
MH  - Humans
MH  - Ion Channel Gating/*genetics
MH  - KCNQ Potassium Channels
MH  - KCNQ1 Potassium Channel
MH  - Long QT Syndrome/*genetics/physiopathology
MH  - *Mutation
MH  - Potassium Channels/*genetics
MH  - *Potassium Channels, Voltage-Gated
MH  - Xenopus
EDAT- 1999/07/20 00:00
MHDA- 1999/07/20 00:01
CRDT- 1999/07/20 00:00
PHST- 1999/07/20 00:00 [pubmed]
PHST- 1999/07/20 00:01 [medline]
PHST- 1999/07/20 00:00 [entrez]
AID - 10.1074/jbc.274.30.21063 [doi]
AID - S0021-9258(19)72547-2 [pii]
PST - ppublish
SO  - J Biol Chem. 1999 Jul 23;274(30):21063-70. doi: 10.1074/jbc.274.30.21063.