Role in fast inactivation of conserved amino acids in the IV/S4-S5 loop of the human muscle Na+ channel.
Since it has been shown that point mutations in the S4-S5 loop of the Shaker K+ channel may disrupt fast inactivation, we investigated the role of three conserved amino acids in IV/S4-S5 of the adult human muscle Na+ channel (L1471, S1478, L1482). In contrast to the K+ channel mutations, the analogous substitutions in the Na+ channel (S1478A/C, L1482A) did not substantially affect fast inactivation. Nevertheless, the mutations S1478A/C/Q shifted the voltage dependence of steady-state inactivation; L1471Q and S1478C slowed recovery from inactivation. In contrast, a novel non-conserved IV/S4-S5 mutation causing paramyotonia congenita (F1473S) slowed fast inactivation 2-fold and accelerated recovery from inactivation 5-fold. The results indicate involvement of the IV/ S4-S5 loop of the human muscle Na+ channel in fast inactivation, but different roles for conserved amino acids among Na+ and K+ channels.
Mitrovic
N
N
Department of Applied Physiology, University of Ulm, Germany.
Lerche
H
H
Heine
R
R
Fleischhauer
R
R
Pika-Hartlaub
U
U
Hartlaub
U
U
George
A L
AL
Lehmann-Horn
F
F
D000595:Amino Acid Sequence; D017124:Conserved Sequence; D006706:Homeostasis; D006801:Humans; D008969:Molecular Sequence Data; D009132:Muscles / Q000378:metabolism*; D009154:Mutation; D009222:Myotonia / Q000235:genetics; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism
D015221:Potassium Channels; D015222:Sodium Channels