Altered KCNQ3 Potassium Channel Function Caused by the W309R Pore-Helix Mutation Found in Human Epilepsy

• Published in: The Journal of membrane biology 2008-03, Vol.222 (2), p.55-63
• Main Authors: Uehara, Akira, Nakamura, Yuki, Shioya, Takao, Hirose, Shinichi, Yasukochi, Midori, Uehara, Kiyoko
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Amino Acid Substitution; Binding Sites; Biochemistry; Biomedical and Life Sciences; Brain - physiopathology; Cell Line; Cellular biology; Electrophysiology; Epilepsy; Epilepsy - genetics; Epilepsy - metabolism; Epilepsy - physiopathology; Heterozygote; Human Physiology; Humans; Hydrogen Bonding; Ion Channel Gating; KCNQ3 Potassium Channel - chemistry; KCNQ3 Potassium Channel - genetics; KCNQ3 Potassium Channel - metabolism; Life Sciences; Membranes; Models, Molecular; Molecular Sequence Data; Mutation; Mutation, Missense; Potassium; Protein Structure, Secondary; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Transfection
• ISSN: 0022-2631; 1432-1424
• DOI: 10.1007/s00232-008-9097-5

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.