The KCNQ2/3 selective channel opener ICA-27243 binds to a novel voltage-sensor domain site

The mammalian KCNQ (Kv7) gene family is composed of five members (KCNQ1–5). KCNQ2, Q4 and Q5 (KCNQ2–5) channels co-express with KCNQ3 to form heterotetrameric voltage-gated K+ (KCNQ2–5/3) channels that underlie the endogenous M-current and regulate neuronal excitability in CNS and PNS neurons. Opene...

Full description

Saved in:
Bibliographic Details
Published in:Neuroscience letters 2009-11, Vol.465 (2), p.138-142
Main Authors: Padilla, Karen, Wickenden, Alan D., Gerlach, Aaron C., McCormack, Ken
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Anticonvulsants - chemistry
Anticonvulsants - pharmacology
Benzamides - chemistry
Benzamides - pharmacology
Binding site
Binding Sites - genetics
Biological and medical sciences
Carbamates - chemistry
Carbamates - pharmacology
CHO Cells
Cricetinae
Cricetulus
Fundamental and applied biological sciences. Psychology
Humans
ICA-27243
K+ channel opener
KCNQ
KCNQ Potassium Channels - genetics
KCNQ Potassium Channels - metabolism
KCNQ2 Potassium Channel - genetics
KCNQ2 Potassium Channel - metabolism
KCNQ3 Potassium Channel - genetics
KCNQ3 Potassium Channel - metabolism
Kv7
Membrane Potentials - drug effects
Membrane Potentials - genetics
Membrane Potentials - physiology
Membrane Transport Modulators - chemistry
Membrane Transport Modulators - pharmacology
Molecular Sequence Data
Mutation
Phenylenediamines - chemistry
Phenylenediamines - pharmacology
Pyridines - chemistry
Pyridines - pharmacology
Retigabine
Sequence Alignment
Sub-type-selective
Tryptophan - genetics
Tryptophan - metabolism
Vertebrates: nervous system and sense organs
Voltage-sensor domain
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The mammalian KCNQ (Kv7) gene family is composed of five members (KCNQ1–5). KCNQ2, Q4 and Q5 (KCNQ2–5) channels co-express with KCNQ3 to form heterotetrameric voltage-gated K+ (KCNQ2–5/3) channels that underlie the endogenous M-current and regulate neuronal excitability in CNS and PNS neurons. Openers of one or a mixture of these channels may be an attractive therapeutic agent for epilepsy and pain. Non-selective KCNQ2–5/3 activators have shown efficacy in pre-clinical and clinical studies. However, more selective pharmacological profiles, including greater KCNQ sub-type-selective activation, could provide efficacy with fewer side effects. One such compound, ICA-27243, sub-type selectively enhances the activation of KCNQ2/3 channels and also exhibits efficacy in pre-clinical anticonvulsant models; Roeloffs et al. (2008) [15]; Wickenden et al. (2008) [27]. The binding site of non-selective KCNQ2–5/3 openers maps to the S5–S6 pore domain and is altered by mutation of a tryptophan residue (Trp236 in KCNQ2, Trp265 in KCNQ3) conserved among KCNQ2–5 channels; Schenzer et al. (2005) [19]; Wuttke et al. (2005) [30]. Here we report that the activity of the KCNQ2/3 selective opener ICA-27243 is not affected by these Trp mutations and does not map to the S5–S6 domain. Rather, the selective activity of ICA-27243 is determined by a novel site within the S1–S4 voltage-sensor domain (VSD) of KCNQ channels. The sub-type-selective activity of ICA-27243 may arise from greater sequence diversity of KCNQ family members within the ICA-27243 binding pocket, allowing for more selective small molecule–protein interactions.
ISSN:0304-3940
1872-7972
DOI:10.1016/j.neulet.2009.08.071