Altered KCNQ3 potassium channel function caused by the W309R pore-helix mutation found in human epilepsy.
The second tryptophan (W) residue of the conserved WW motif in the pore helix of many K+ channel subunit is thought to interact with the tyrosine (Y) residues of the selectivity filter. A missense mutation causing the replacement of the corresponding residues with an arginine (W309R) occurs in KCNQ3 subunits forming part of M-channels. In this study, we examined the functional consequences of the W309R mutation in heterogously expressed KCNQ channels. Homomeric KCNQ3W309R channels lacked KCNQ currents. Heteromeric KCNQ2/KCNQ3W309R channels displayed a dominant-negative suppression of current and a significant modification in gating properties when compared with heteromeric KCNQ3/KCNQ2 channels mimicking the M-channels. A three-dimensional homology model in the W309R mutant indicated that the R side chain of pore helices is too far from the Y side chain of the selectivity filter to interact via hydrogen bonds with each other and stabilize the pore structure. Collectively, the present results suggest that the second W residues of pore helices and their chemical interaction with the Y residues of the selectivity filter are essential for normal K+ channel function. This pore-helix mutation, if occurs in the brain M channels, could thus lead to a channel dysfunction sufficient to trigger epileptic hyperexcitability.
Uehara
Akira
A
Department of Physiology, School of Medicine, Fukuoka University, 45-1, 7-chome Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan. ueharaak@fukuoka-u.ac.jp
Nakamura
Yuki
Y
Shioya
Takao
T
Hirose
Shinichi
S
Yasukochi
Midori
M
Uehara
Kiyoko
K
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001665:Binding Sites; D001921:Brain / Q000503:physiopathology; D002460:Cell Line; D004594:Electrophysiology; D004827:Epilepsy / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D006579:Heterozygote; D006801:Humans; D006860:Hydrogen Bonding; D015640:Ion Channel Gating; D051659:KCNQ3 Potassium Channel / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D051659:KCNQ3 Potassium Channel; C496916:KCNQ3 protein, human; D011994:Recombinant Proteins