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

Padilla, Karen; Wickenden, Alan D.; Gerlach, Aaron C.; McCormack, Ken

doi:10.1016/j.neulet.2009.08.071

Cited by 73 publications

(106 citation statements)

References 30 publications

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“…This notion is reminiscent to the finding that a point mutation (S512Y), in the S1-S2 loop converts the VSD targeted TRPV1 antagonist iodoresiniferatoxin into an intrinsic agonist (26). Our data are in line with a very recent study suggesting that the Kv7.2/3 channel opener ICA-27243 may interact with the VSD (27).…”

Section: Discussionsupporting

confidence: 90%

Targeting the voltage sensor of Kv7.2 voltage-gated K ⁺ channels with a new gating-modifier

Peretz

Pell

Gofman

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

116

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The pore and gate regions of voltage-gated cation channels have been often targeted with drugs acting as channel modulators. In contrast, the voltage-sensing domain (VSD) was practically not exploited for therapeutic purposes, although it is the target of various toxins. We recently designed unique diphenylamine carboxylates that are powerful Kv7.2 voltage-gated K + channel openers or blockers. Here we show that a unique Kv7.2 channel opener, NH29, acts as a nontoxin gating modifier. NH29 increases Kv7.2 currents, thereby producing a hyperpolarizing shift of the activation curve and slowing both activation and deactivation kinetics. In neurons, the opener depresses evoked spike discharges. NH29 dampens hippocampal glutamate and GABA release, thereby inhibiting excitatory and inhibitory postsynaptic currents. Mutagenesis and modeling data suggest that in Kv7.2, NH29 docks to the external groove formed by the interface of helices S1, S2, and S4 in a way that stabilizes the interaction between two conserved charged residues in S2 and S4, known to interact electrostatically, in the open state of Kv channels. Results indicate that NH29 may operate via a voltagesensor trapping mechanism similar to that suggested for scorpion and sea-anemone toxins. Reflecting the promiscuous nature of the VSD, NH29 is also a potent blocker of TRPV1 channels, a feature similar to that of tarantula toxins. Our data provide a structural framework for designing unique gating-modifiers targeted to the VSD of voltage-gated cation channels and used for the treatment of hyperexcitability disorders.oltage-sensitive cation channels play crucial roles in brain and cardiac excitability. These channels are endowed with two main transmembrane modules, a voltage-sensing domain (VSD) and a pore domain. Mutations of ion channel genes in humans lead to severe inherited neurological, cardiovascular, or metabolic disorders, called "channelopathies" (1). So far, the medicinal toolbox has focused on the pore domain and its gate in an attempt to cure ion channel-related dysfunctions by channel blockers or openers (2).In contrast, the VSD of voltage-gated cation channels was virtually not exploited for therapeutic purposes. VSDs are found in voltage-dependent cation channels and other voltage-regulated proteins (3). In voltage-gated cation channels, the linker S4-S5 of the VSD serves as an electromechanical coupling device, which opens the channel pore. VSDs have also been recently characterized in voltage-regulated proteins that lack associated ion channel pores (4-6). A voltage-sensitive phosphatase, Ci-VSP, has a VSD that is coupled to a phosphatase domain (4). In the human voltage-activated proton channel (Hv1), the VSD itself functions as a proton channel (5-7).Crystallographic studies of voltage-gated K + channels (Kv) have described the VSD architecture in its open-state conformation. It forms a module of four membrane-spanning segments (S1-S4) with the S3b helix and the charge-bearing S4 helix forming a helix-turn-helix structure, termed the "paddle ...

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Section: Discussionsupporting

confidence: 90%

Targeting the voltage sensor of Kv7.2 voltage-gated K ⁺ channels with a new gating-modifier

Peretz

Pell

Gofman

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

116

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“…Gating modifiers of Kv7 channels include two groups of structurally unrelated compounds: N-pyridyl and pyrimidine benzamides (ICA-27243, ICA-069673, and ztz240) and N-phenylanthranilic acid derivatives (diclofenac, meclofenamic acid (2-[(2,6-dichloro-3-methylphenyl) amino]benzoic acid), and NH29 (2-[(2, 6-dichloro-4-nitrophenyl)amino]-N-(hydroxymethyl)-3,5-dinitrobenzamide) (Peretz et al, 2007;Wickenden et al, 2008;Padilla et al, 2009;Peretz et al, 2010;Gao et al, 2010;Amato et al, 2011;Li et al, 2013). ICA-069673 and ICA-27243 have similar structures, sharing the same two fluorines in a phenyl ring and an amide linker between aromatic rings, but ICA-27243 has a 6-chloro-pyridine ring, whereas ICA-069673 has a 2-chloro-5-aminopyrimidine ring (Amato et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…ICA-27243 (N-(6-chloropyridin-3-yl)-3,4-difluorobenzamide) was found to be 20-fold more potent as an activator of heteromeric Kv7.2/7.3 channels than homomeric Kv7.4 channels, unable to activate homomeric Kv7.3, and only a weak activator of heteromeric Kv7.3/7.5 channels (Wickenden et al, 2008;Padilla et al, 2009;Blom et al, 2010). Unfortunately, the efficacy of ICA-27243 on homomeric Kv7.5 and heteromeric Kv7.4/7.5 was not evaluated.…”

Section: Introductionmentioning

confidence: 99%

Differential Activation of Vascular Smooth Muscle Kv7.4, Kv7.5, and Kv7.4/7.5 Channels by ML213 and ICA-069673

et al. 2014

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Recent research suggests that smooth muscle cells express Kv7.4 and Kv7.5 voltage-activated potassium channels, which contribute to maintenance of their resting membrane voltage. New pharmacologic activators of Kv7 channels, ML213 (N-mesitybicyclo[2.2.1]heptane-2-carboxamide) and ICA-069673 N-(6-chloropyridin-3-yl)-3,4-difluorobenzamide), have been reported to discriminate among channels formed from different Kv7 subtypes. We compared the effects of ML213 and ICA-069673 on homomeric human Kv7.4, Kv7.5, and heteromeric Kv7.4/7.5 channels exogenously expressed in A7r5 vascular smooth muscle cells. We found that, despite its previous description as a selective activator of Kv7.2 and Kv7.4, ML213 significantly increased the maximum conductance of homomeric Kv7.4 and Kv7.5, as well as heteromeric Kv7.4/7.5 channels, and induced a negative shift of their activation curves. Current deactivation rates decreased in the presence of the ML213 (10 mM) for all three channel combinations. Mutants of Kv7.4 (W242L) and Kv7.5 (W235L), previously found to be insensitive to another Kv7 channel activator, retigabine, were also insensitive to ML213 (10 mM). In contrast to ML213, ICA-069673 robustly activated Kv7.4 channels but was significantly less effective on homomeric Kv7.5 channels. Heteromeric Kv7.4/7.5 channels displayed intermediate responses to ICA-069673. In each case, ICA-069673 induced a negative shift of the activation curves without significantly increasing maximal conductance. Current deactivation rates decreased in the presence of ICA-069673 in a subunit-specific manner. Kv7.4 W242L responded to ICA-069673-like wild-type Kv7.4, but a Kv7.4 F143A mutant was much less sensitive to ICA-069673. Based on these results, ML213 and ICA-069673 likely bind to different sites and are differentially selective among Kv7.4, Kv7.5, and Kv7.4/7.5 channel subtypes.

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“…Besides retigabine and ZnPy, there are several compounds capable of augmenting KCNQ channels, and several different key residues conferring the drug sensitivity have been identified (19). Indeed, some of these drugs, although different from ZnPy, also augment the KCNQ2 W236L mutant channels, e.g., ztz240 and ICA-27243 (20)(21)(22). Recent evidence suggests a direct drug-channel interaction with the voltage-sensing domain (VSD) (23).…”

Section: W236lmentioning

confidence: 99%

Phosphatidylinositol 4,5-bisphosphate alters pharmacological selectivity for epilepsy-causing KCNQ potassium channels

Zhou

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Pharmacological augmentation of neuronal KCNQ muscarinic (M) currents by drugs such as retigabine (RTG) represents a first-in-class therapeutic to treat certain hyperexcitatory diseases by dampening neuronal firing. Whereas all five potassium channel subtypes (KCNQ1-KCNQ5) are found in the nervous system, KCNQ2 and KCNQ3 are the primary players that mediate M currents. We investigated the plasticity of subtype selectivity by two M current effective drugs, retigabine and zinc pyrithione (ZnPy). Retigabine is more effective on KCNQ3 than KCNQ2, whereas ZnPy is more effective on KCNQ2 with no detectable effect on KCNQ3. In neurons, activation of muscarinic receptor signaling desensitizes effects by retigabine but not ZnPy. Importantly, reduction of phosphatidylinositol 4,5-bisphosphate (PIP 2 ) causes KCNQ3 to become sensitive to ZnPy but lose sensitivity to retigabine. The dynamic shift of pharmacological selectivity caused by PIP 2 may be induced orthogonally by voltagesensitive phosphatase, or conversely, abolished by mutating a PIP 2 site within the S4-S5 linker of KCNQ3. Therefore, whereas drugchannel binding is a prerequisite, the drug selectivity on M current is dynamic and may be regulated by receptor signaling pathways via PIP 2 . . They open at subthreshold voltages and the channel activity is functionally down-regulated by G protein coupled receptor (GPCR) signaling pathways through intracellular secondary messengers, primarily phosphatidylinositol 4,5-bisphosphate (PIP 2 ) (1, 2). In the nervous system, KCNQ2 and KCNQ3 subtypes are major determinants for potassium current sensitive to muscarinic (M) receptor signaling, hence also known as M current (3). The combination of sensitivity to subthreshold voltages and down-regulation by receptor signaling makes M current a critical component for controlling membrane potential in the nervous system, and consequently neuronal firing (4-6). KCNQ2-5 channels, with few exceptions (7), are primarily expressed in the brain and peripheral nervous system. KCNQ1, although it is found in brain (8), is more abundantly expressed in the heart to mediate slow delayed rectifier K + current (also known as I Ks ) that contributes to the termination of action potential, hence regulating QT duration (9).Retigabine (RTG) or ethyl N-[2-amino-4-[(4-fluorophenyl) methylamino] phenyl]carbamate, a positive allosteric modulator (or an opener) for neuronal KCNQ channel, is a first-in-class therapeutic for antiepileptic treatment (10-12). Its clinical use to dampen the hyperexcitatory activity has greatly intensified the interest in a more detailed understanding of chemical augmentation of voltage-sensitive channel activity. Retigabine has selectivity for KCNQ2, -3, -4, and -5 potassium channels but not KCNQ1 potassium channels (13). Tryptophan (W) 236 in KCNQ2 is conserved among the sensitive channels. Interestingly, KCNQ2 channels with W236L mutation (or KCNQ2 W236L ) are functional but no longer sensitive to retigabine (14,15). This and other evidence supports the idea that W236 is a ...

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

Cited by 73 publications

References 30 publications

Targeting the voltage sensor of Kv7.2 voltage-gated K ⁺ channels with a new gating-modifier

Targeting the voltage sensor of Kv7.2 voltage-gated K ⁺ channels with a new gating-modifier

Differential Activation of Vascular Smooth Muscle Kv7.4, Kv7.5, and Kv7.4/7.5 Channels by ML213 and ICA-069673

Phosphatidylinositol 4,5-bisphosphate alters pharmacological selectivity for epilepsy-causing KCNQ potassium channels

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

Cited by 73 publications

References 30 publications

Targeting the voltage sensor of Kv7.2 voltage-gated K + channels with a new gating-modifier

Targeting the voltage sensor of Kv7.2 voltage-gated K + channels with a new gating-modifier

Differential Activation of Vascular Smooth Muscle Kv7.4, Kv7.5, and Kv7.4/7.5 Channels by ML213 and ICA-069673

Phosphatidylinositol 4,5-bisphosphate alters pharmacological selectivity for epilepsy-causing KCNQ potassium channels

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Targeting the voltage sensor of Kv7.2 voltage-gated K ⁺ channels with a new gating-modifier

Targeting the voltage sensor of Kv7.2 voltage-gated K ⁺ channels with a new gating-modifier