PMID- 10644771
OWN - NLM
STAT- MEDLINE
DCOM- 20000229
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 275
IP  - 4
DP  - 2000 Jan 28
TI  - Mechanism of inverted activation of ClC-1 channels caused by a novel myotonia
      congenita mutation.
PG  - 2999-3005
AB  - The voltage-gated chloride channel ClC-1 is the major contributor of membrane
      conductance in skeletal muscle and has been associated with the inherited
      muscular disorder myotonia congenita. Here, we report a novel mutation identified
      in a recessive myotonia congenita family. This mutation, Gly-499 to Arg (G499R)
      is located in the putative transmembrane domain 10 of the ClC-1 protein. In
      contrast to normal ClC-1 channels that deactivate upon hyperpolarization,
      functional expression of G499R ClC-1 yielded a hyperpolarization-activated
      chloride current when measured in the presence of a high (134 mM) intracellular
      chloride concentration. Current was abolished when measured with a physiological 
      chloride transmembrane gradient. Electrophysiological analysis of other Gly-499
      mutants (G499K, G499Q, and G499E) suggests that the positive charge introduced by
      the G499R mutation may be responsible for this unique gating behavior. To further
      explore the function of domain 10, we mutated two charged residues near Gly-499
      of ClC-1. Functional analyses of R496Q, R496Q/G499R, R496K, and E500Q mutant
      channels suggest that the charged residues in domain 10 are important for normal 
      channel function. Study of these mutants may shed further light on the structure 
      and voltage-gating of this channel.
FAU - Zhang, J
AU  - Zhang J
AD  - Department of Neurology, University of Utah, Salt Lake City, Utah 84112, USA.
FAU - Sanguinetti, M C
AU  - Sanguinetti MC
FAU - Kwiecinski, H
AU  - Kwiecinski H
FAU - Ptacek, L J
AU  - Ptacek LJ
LA  - eng
GR  - MO1-RR00064/RR/NCRR 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 (CLC-1 channel)
RN  - 0 (Chloride Channels)
SB  - IM
MH  - Cell Line
MH  - Chloride Channels/*genetics/physiology
MH  - Gene Expression Regulation/*genetics
MH  - Humans
MH  - Membrane Potentials
MH  - Mutagenesis, Site-Directed
MH  - Myotonia Congenita/*genetics
MH  - *Point Mutation
MH  - Polymorphism, Single-Stranded Conformational
EDAT- 2000/01/25 09:00
MHDA- 2000/03/04 09:00
CRDT- 2000/01/25 09:00
PHST- 2000/01/25 09:00 [pubmed]
PHST- 2000/03/04 09:00 [medline]
PHST- 2000/01/25 09:00 [entrez]
AID - 10.1074/jbc.275.4.2999 [doi]
AID - S0021-9258(18)31066-4 [pii]
PST - ppublish
SO  - J Biol Chem. 2000 Jan 28;275(4):2999-3005. doi: 10.1074/jbc.275.4.2999.