PMID- 10187793
OWN - NLM
STAT- MEDLINE
DCOM- 19990503
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 274
IP  - 15
DP  - 1999 Apr 9
TI  - Long QT syndrome-associated mutations in the Per-Arnt-Sim (PAS) domain of HERG
      potassium channels accelerate channel deactivation.
PG  - 10113-8
AB  - Mutations in the human ether-a-go-go-related gene (HERG) cause long QT syndrome, 
      an inherited disorder of cardiac repolarization that predisposes affected
      individuals to life-threatening arrhythmias. HERG encodes the cardiac rapid
      delayed rectifier potassium channel that mediates repolarization of ventricular
      action potentials. In this study, we used the oocyte expression system and
      voltage clamp techniques to determine the functional consequences of eight long
      QT syndrome-associated mutations located in the amino-terminal region of HERG
      (F29L, N33T, G53R, R56Q, C66G, H70R, A78P, and L86R). Mutant subunits formed
      functional channels with altered gating properties when expressed alone in
      oocytes. Deactivation was accelerated by all mutations. Some mutants shifted the 
      voltage dependence of channel availability to more positive potentials. Voltage
      ramps indicated that fast deactivation of mutant channels would reduce outward
      current during the repolarization phase of the cardiac action potential and cause
      prolongation of the corrected QT interval, QTc. The amino-terminal region of HERG
      was recently crystallized and shown to possess a Per-Arnt-Sim (PAS) domain. The
      location of these mutations suggests they may disrupt the PAS domain and
      interfere with its interaction with the S4-S5 linker of the HERG channel.
FAU - Chen, J
AU  - Chen J
AD  - Department of Medicine, Division of Cardiology, University of Utah, Salt Lake
      City, Utah 84112, USA.
FAU - Zou, A
AU  - Zou A
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, Non-U.S. Gov't
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 (Basic Helix-Loop-Helix Transcription Factors)
RN  - 0 (Cation Transport Proteins)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (ERG protein, human)
RN  - 0 (ERG1 Potassium Channel)
RN  - 0 (Ether-A-Go-Go Potassium Channels)
RN  - 0 (KCNH2 protein, human)
RN  - 0 (KCNH6 protein, human)
RN  - 0 (Potassium Channels)
RN  - 0 (Potassium Channels, Voltage-Gated)
RN  - 0 (Trans-Activators)
RN  - 0 (Transcriptional Regulator ERG)
RN  - 1B37H0967P (endothelial PAS domain-containing protein 1)
SB  - IM
MH  - Animals
MH  - Basic Helix-Loop-Helix Transcription Factors
MH  - *Cation Transport Proteins
MH  - *DNA-Binding Proteins
MH  - ERG1 Potassium Channel
MH  - Ether-A-Go-Go Potassium Channels
MH  - Helix-Loop-Helix Motifs
MH  - Humans
MH  - Long QT Syndrome/*genetics
MH  - *Mutation
MH  - Oocytes/metabolism
MH  - Potassium Channels/*genetics
MH  - *Potassium Channels, Voltage-Gated
MH  - Protein Conformation
MH  - Protein Structure, Tertiary
MH  - *Sequence Homology, Amino Acid
MH  - Structure-Activity Relationship
MH  - Trans-Activators/chemistry
MH  - Transcriptional Regulator ERG
MH  - Transfection
MH  - Xenopus laevis
EDAT- 1999/04/03 00:00
MHDA- 1999/04/03 00:01
CRDT- 1999/04/03 00:00
PHST- 1999/04/03 00:00 [pubmed]
PHST- 1999/04/03 00:01 [medline]
PHST- 1999/04/03 00:00 [entrez]
AID - 10.1074/jbc.274.15.10113 [doi]
AID - S0021-9258(19)73691-6 [pii]
PST - ppublish
SO  - J Biol Chem. 1999 Apr 9;274(15):10113-8. doi: 10.1074/jbc.274.15.10113.