Gating currents from Kv7 channels carrying neuronal hyperexcitability mutations in the voltage-sensing domain.

Abstract

Changes in voltage-dependent gating represent a common pathogenetic mechanism for genetically inherited channelopathies, such as benign familial neonatal seizures or peripheral nerve hyperexcitability caused by mutations in neuronal K(v)7.2 channels. Mutation-induced changes in channel voltage dependence are most often inferred from macroscopic current measurements, a technique unable to provide a detailed assessment of the structural rearrangements underlying channel gating behavior; by contrast, gating currents directly measure voltage-sensor displacement during voltage-dependent gating. In this work, we describe macroscopic and gating current measurements, together with molecular modeling and molecular-dynamics simulations, from channels carrying mutations responsible for benign familial neonatal seizures and/or peripheral nerve hyperexcitability; K(v)7.4 channels, highly related to K(v)7.2 channels both functionally and structurally, were used for these experiments. The data obtained showed that mutations affecting charged residues located in the more distal portion of S(4) decrease the stability of the open state and the active voltage-sensing domain configuration but do not directly participate in voltage sensing, whereas mutations affecting a residue (R4) located more proximally in S(4) caused activation of gating-pore currents at depolarized potentials. These results reveal that distinct molecular mechanisms underlie the altered gating behavior of channels carrying disease-causing mutations at different voltage-sensing domain locations, thereby expanding our current view of the pathogenesis of neuronal hyperexcitability diseases.

• Authors: Francesco Miceli, Ernesto Vargas, Francisco Bezanilla, Maurizio Taglialatela
• Journal: Biophysical journal (Biophys J) Vol. 102 Issue 6 Pg. 1372-82 (Mar 21 2012) ISSN: 1542-0086 [Electronic] United States
• PMID: 22455920 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Chemical References

• KCNQ2 Potassium Channel
• Mutant Proteins

Topics

• Amino Acid Sequence
• Amino Acid Substitution (genetics)
• Animals
• Humans
• Ion Channel Gating (physiology)
• KCNQ2 Potassium Channel (chemistry, genetics, metabolism)
• Membrane Potentials (physiology)
• Molecular Dynamics Simulation
• Molecular Sequence Data
• Mutant Proteins (chemistry, metabolism)
• Mutation (genetics)
• Neurons (physiology)
• Protein Structure, Tertiary
• Structure-Activity Relationship
• Xenopus