title: The KCNQ2/3 selective channel opener ICA-27243 binds to a novel voltage-sensor domain site.
abstract: 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.
authors.affiliation: Icagen, 4222 Emperor Boulevard, Suite 460, Durham, NC 27703, United States. kpadilla@icagen.com
authors.forename: Karen
authors.initials: K
authors.lastname: Padilla
authors.forename: Alan D
authors.initials: AD
authors.lastname: Wickenden
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Gerlach
authors.forename: Ken
authors.initials: K
authors.lastname: McCormack
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry / Q000494:pharmacology; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000235:genetics; D016466:CHO Cells; D002219:Carbamates / Q000737:chemistry / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D051656:KCNQ Potassium Channels / Q000235:genetics / Q000378:metabolism; D051658:KCNQ2 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D051659:KCNQ3 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D049990:Membrane Transport Modulators / Q000737:chemistry / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009154:Mutation; D010655:Phenylenediamines / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D016415:Sequence Alignment; D014364:Tryptophan / Q000235:genetics / Q000378:metabolism
chemical_list: D000927:Anticonvulsants; D001549:Benzamides; D002219:Carbamates; D051656:KCNQ Potassium Channels; D051658:KCNQ2 Potassium Channel; C496914:KCNQ2 protein, human; D051659:KCNQ3 Potassium Channel; C496916:KCNQ3 protein, human; C412231:KCNQ5 protein, human; D049990:Membrane Transport Modulators; C527835:N-(6-Chloropyridin-3-yl)-3,4-difluorobenzamide; D010655:Phenylenediamines; D011725:Pyridines; C101866:ezogabine; D014364:Tryptophan