RT Journal Article
SR Electronic
T1 Molecular Determinants of KCNQ (K<sub>v</sub>7) K<sup>+</sup> Channel Sensitivity to the Anticonvulsant Retigabine
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 5051
OP 5060
DO 10.1523/JNEUROSCI.0128-05.2005
VO 25
IS 20
A1 Schenzer, Anne
A1 Friedrich, Thomas
A1 Pusch, Michael
A1 Saftig, Paul
A1 Jentsch, Thomas J.
A1 Grötzinger, Joachim
A1 Schwake, Michael
YR 2005
UL http://www.jneurosci.org/content/25/20/5051.abstract
AB Epilepsy is caused by an electrical hyperexcitability in the CNS. Because K+ channels are critical for establishing and stabilizing the resting potential of neurons, a loss of K+ channels could support neuronal hyperexcitability. Indeed, benign familial neonatal convulsions, an autosomal dominant epilepsy of infancy, is caused by mutations in KCNQ2 or KCNQ3 K+ channel genes. Because these channels contribute to the native muscarinic-sensitive K+ current (M current) that regulates excitability of numerous types of neurons, KCNQ (Kv7) channel activators would be effective in epilepsy treatment. A compound exhibiting anticonvulsant activity in animal seizure models is retigabine. It specifically acts on the neuronally expressed KCNQ2-KCNQ5 (Kv7.2-Kv7.5) channels, whereas KCNQ1 (Kv7.1) is not affected. Using the differential sensitivity of KCNQ3 and KCNQ1 to retigabine, we constructed chimeras to identify minimal segments required for sensitivity to the drug. We identified a single tryptophan residue within the S5 segment of KCNQ3 and also KCNQ2, KCNQ4, and KCNQ5 as crucial for the effect of retigabine. Furthermore, heteromeric KCNQ channels comprising KCNQ2 and KCNQ1 transmembrane domains (attributable to transfer of assembly properties from KCNQ3 to KCNQ1) are retigabine insensitive. Transfer of the tryptophan into the KCNQ1 scaffold resulted in retigabine-sensitive heteromers, suggesting that the tryptophan is necessary in all KCNQ subunits forming a functional tetramer to confer drug sensitivity.