Journal
BIOPHYSICAL JOURNAL
Volume 95, Issue 5, Pages 2254-2264Publisher
CELL PRESS
DOI: 10.1529/biophysj.107.128371
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Funding
- NINDS NIH HHS [R01 NS043394] Funding Source: Medline
- Telethon [GGP07125] Funding Source: Medline
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The K(v)7.2 subunits are the main molecular determinants of the M-current, a widespread K+ current regulating neuronal excitability. Mutations in the K(v)7.2 gene cause benign familial neonatal seizures, an autosomally inherited human epilepsy. The benign familial neonatal seizure-causing mutations include those at arginine residues at positions 207 and 214 in the S-4 segment of K(v)7.2. In this study, each of the six S-4 arginines was individually replaced with neutral glutamines, and the functional properties of mutant channels were studied by whole-cell and single-channel voltage-clamp measurements. The results obtained suggest that each S-4 arginine residue plays a relevant role in the voltage-dependent gating of K(v)7.2 channels. In particular, a decreased positive charge at the N-terminal end of S-4 stabilized the activated state of the voltage-sensor, whereas positive-charge neutralization at the C-terminal end of S-4 favored the resting conformation. Strikingly, neutralization of a single arginine at position 201 was sufficient to cause a significant loss of voltage dependence in channel activation. Moreover, by comparing the functional properties of glutamine versus tryptophan substitution, we found steric bulk to play a relevant role at position 207, but not at position 214, in which the main functional effect of this disease-causing mutation seems to be a consequence of the loss of the positive charge.
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