PMID- 10618304
OWN - NLM
STAT- MEDLINE
DCOM- 20000224
LR  - 20190623
IS  - 0009-7322 (Print)
IS  - 0009-7322 (Linking)
VI  - 101
IP  - 1
DP  - 2000 Jan 4-11
TI  - Cardiac Na(+) channel dysfunction in Brugada syndrome is aggravated by
      beta(1)-subunit.
PG  - 54-60
AB  - BACKGROUND: Mutations in the gene encoding the human cardiac Na(+) channel
      alpha-subunit (hH1) are responsible for chromosome 3-linked congenital long-QT
      syndrome (LQT3) and idiopathic ventricular fibrillation (IVF). An auxiliary
      beta(1)-subunit, widely expressed in excitable tissues, shifts the voltage
      dependence of steady-state inactivation toward more negative potentials and
      restores normal gating kinetics of brain and skeletal muscle Na(+) channels
      expressed in Xenopus oocytes but has little if any functional effect on the
      cardiac isoform. Here, we characterize the altered effects of a human
      beta(1)-subunit (hbeta(1)) on the heterologously expressed hH1 mutation (T1620M) 
      previously associated with IVF. METHODS AND RESULTS: When expressed alone in
      Xenopus oocytes, T1620M exhibited no persistent currents, in contrast to the LQT3
      mutant channels, but the midpoint of steady-state inactivation (V(1/2)) was
      significantly shifted toward more positive potentials than for wild-type hH1.
      Coexpression of hbeta(1) did not significantly alter current decay or recovery
      from inactivation of wild-type hH1; however, it further shifted the V(1/2) and
      accelerated the recovery from inactivation of T1620M. Oocyte macropatch analysis 
      revealed that the activation kinetics of T1620M were normal. CONCLUSIONS: It is
      suggested that coexpression of hbeta(1) exposes a more severe functional defect
      that results in a greater overlap in the relationship between channel
      inactivation and activation (window current) in T1620M, which is proposed to be a
      potential pathophysiological mechanism of IVF in vivo. One possible explanation
      for our finding is an altered alpha-/beta(1)-subunit association in the mutant.
FAU - Makita, N
AU  - Makita N
AD  - Department of Cardiovascular Medicine, Hokkaido University School of Medicine,
      Sapporo, Japan. makitan@med.hokudai.ac.jp
FAU - Shirai, N
AU  - Shirai N
FAU - Wang, D W
AU  - Wang DW
FAU - Sasaki, K
AU  - Sasaki K
FAU - George, A L Jr
AU  - George AL Jr
FAU - Kanno, M
AU  - Kanno M
FAU - Kitabatake, A
AU  - Kitabatake A
LA  - eng
GR  - NS32387/NS/NINDS 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  - Circulation
JT  - Circulation
JID - 0147763
RN  - 0 (Macromolecular Substances)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Sodium Channels)
SB  - IM
MH  - Amino Acid Substitution
MH  - Animals
MH  - Cell Membrane/physiology
MH  - Chromosome Mapping
MH  - *Chromosomes, Human, Pair 3
MH  - Heart/*physiopathology
MH  - Humans
MH  - Ion Channel Gating
MH  - Kinetics
MH  - Long QT Syndrome/*genetics/physiopathology
MH  - Macromolecular Substances
MH  - Membrane Potentials
MH  - Myocardium/metabolism
MH  - Oocytes/physiology
MH  - Protein Structure, Secondary
MH  - Recombinant Proteins/chemistry/metabolism
MH  - Sodium Channels/chemistry/*genetics/*physiology
MH  - Syndrome
MH  - Ventricular Fibrillation/*genetics/physiopathology
MH  - Xenopus
EDAT- 2000/01/05 09:00
MHDA- 2000/02/26 09:00
CRDT- 2000/01/05 09:00
PHST- 2000/01/05 09:00 [pubmed]
PHST- 2000/02/26 09:00 [medline]
PHST- 2000/01/05 09:00 [entrez]
AID - 10.1161/01.cir.101.1.54 [doi]
PST - ppublish
SO  - Circulation. 2000 Jan 4-11;101(1):54-60. doi: 10.1161/01.cir.101.1.54.