An aspartic acid residue important for voltage-dependent gating of human muscle chloride channels.
A point mutation (D136G) predicting the substitution of glycine for aspartate in position 136 of the human muscle Cl- channel (hClC-1) causes recessive generalized myotonia. Heterologous expression of a recombinant D136G produces functional Cl- channels with profound alterations in voltage-dependent gating, without concomitant changes in pore properties. The mutant exhibits slowly activating current upon hyperpolarization, in contrast to wild-type channels, which display time-dependent current decay (deactivation) at negative membrane potentials. Steady-state activation of D136G depends upon the transmembrane Cl- gradient, reaching zero at voltages positive to the Cl- reversal potential in physiological Cl- distribution. This explains the reduced sarcolemmal Cl- conductance that causes myotonia. The functional disturbances exhibited by D136G may stem from a defect in the ClC-1 voltage sensor.
Fahlke
C
C
Department of General Physiology, University of Ulm, Federal Republic of Germany.
Rüdel
R
R
Mitrovic
N
N
Zhou
M
M
George
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AL
D000200:Action Potentials; D000818:Animals; D001224:Aspartic Acid / Q000502:physiology*; D001483:Base Sequence; D002461:Cell Line, Transformed; D018118:Chloride Channels / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology*; D007668:Kidney; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D009224:Myotonia Congenita / Q000235:genetics* / Q000503:physiopathology; D009865:Oocytes; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011487:Protein Conformation; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012508:Sarcolemma / Q000378:metabolism; D013329:Structure-Activity Relationship; D014162:Transfection; D014982:Xenopus laevis
C086321:CLC-1 channel; D018118:Chloride Channels; D018076:DNA, Complementary; D009124:Muscle Proteins; D011993:Recombinant Fusion Proteins; D001224:Aspartic Acid