Altered KCNQ3 potassium channel function caused by the W309R pore-helix mutation found in human epilepsy.

Abstract

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.

• Authors: Akira Uehara, Yuki Nakamura, Takao Shioya, Shinichi Hirose, Midori Yasukochi, Kiyoko Uehara
• Journal: The Journal of membrane biology (J Membr Biol) Vol. 222 Issue 2 Pg. 55-63 (Mar 2008) ISSN: 0022-2631 [Print] United States
• PMID: 18425618 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• KCNQ3 Potassium Channel
• KCNQ3 protein, human
• Recombinant Proteins

Topics

• Amino Acid Sequence
• Amino Acid Substitution
• Binding Sites
• Brain (physiopathology)
• Cell Line
• Electrophysiology
• Epilepsy (genetics, metabolism, physiopathology)
• Heterozygote
• Humans
• Hydrogen Bonding
• Ion Channel Gating
• KCNQ3 Potassium Channel (chemistry, genetics, metabolism)
• Models, Molecular
• Molecular Sequence Data
• Mutation, Missense
• Protein Structure, Secondary
• Recombinant Proteins (chemistry, genetics, metabolism)
• Transfection