Molecular Determinants of KCNQ (Kv7) K+Channel Sensitivity to the Anticonvulsant Retigabine

• DOI: 10.1523/jneurosci.0128-05.2005
• Publication Date: 2005-05-18T18:28:49Z
• Authors: Anne Schenzer; Thomas Friedrich; Michael Pusch; Paul Saftig; Thomas J. Jentsch; Joachim Grötzinger; Michael Schwake
• Keywords: Models, Molecular; 0301 basic medicine; Patch-Clamp Techniques; KCNQ2/KCNQ3; Microinjections; Phenylenediamines; Membrane Potentials; 03 medical and health sciences; IDIOPATHIC EPILEPSY; Animals; Humans; Point Mutation; TRAFFICKING; Cloning, Molecular; Dose-Response Relationship, Drug; KCNQ Potassium Channels; Tryptophan; Dose-Response Relationship, Radiation; SUBUNITS; Electric Stimulation; Protein Structure, Tertiary; Mutagenesis; Oocytes; POTASSIUM CHANNEL; Anticonvulsants; Carbamates; Sequence Alignment

Epilepsy is caused by an electrical hyperexcitability in the CNS. Because K + channels are critical for establishing and stabilizing resting potential of neurons, a loss could support neuronal hyperexcitability. Indeed, benign familial neonatal convulsions, autosomal dominant epilepsy infancy, mutations KCNQ2 or KCNQ3 channel genes. these contribute to native muscarinic-sensitive current (M current) that regulates excitability numerous types KCNQ (K v 7) activators would be effective treatment. A compound exhibiting anticonvulsant activity animal seizure models retigabine. It specifically acts on neuronally expressed KCNQ2-KCNQ5 7.2-K 7.5) channels, whereas KCNQ1 7.1) not affected. Using differential sensitivity retigabine, we constructed chimeras identify minimal segments required drug. We identified single tryptophan residue within S5 segment also KCNQ2, KCNQ4, KCNQ5 as crucial effect Furthermore, heteromeric comprising transmembrane domains (attributable transfer assembly properties from KCNQ1) retigabine insensitive. Transfer into scaffold resulted retigabine-sensitive heteromers, suggesting necessary all subunits forming functional tetramer confer drug sensitivity.