Atomic basis for therapeutic activation of neuronal potassium channels

Kim, Robin Y.; Yau, Michael C.; Galpin, Jason D.; Seebohm, Guiscard; Ahern, Christopher A.; Pless, Stephan A.; Kurata, Harley T.

doi:10.1038/ncomms9116

Cited by 71 publications

(95 citation statements)

References 52 publications

(82 reference statements)

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“…Whereas it was thought that the critical property of W was its hydrophobicity (Wuttke et al, 2005), recent studies have revealed that the ability of W to form H-bonds with the carbonyl/carbamate oxygen atom present in retigabine makes this contact critical (Kim et al, 2015). These studies suggest that the strength of the H-bond between retigabine and W236 determines the potency of retigabine.…”

Section: Discussionmentioning

confidence: 85%

Synthesis and Evaluation of Potent KCNQ2/3-Specific Channel Activators

et al. 2016

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KQT-like subfamily (KCNQ) channels are voltage-gated, noninactivating potassium ion channels, and their down-regulation has been implicated in several hyperexcitability-related disorders, including epilepsy, neuropathic pain, and tinnitus. Activators of these channels reduce the excitability of central and peripheral neurons, and, as such, have therapeutic utility. Here, we synthetically modified several moieties of the KCNQ2-5 channel activator retigabine, an anticonvulsant approved by the U.S. Food and Drug Administration. By introducing a CF 3 -group at the 4-position of the benzylamine moiety, combined with a fluorine atom at the 3-position of the aniline ring, we generated Ethyl (2-amino-3-fluoro-4-((4-(trifluoromethyl)benzyl)amino)phenyl)carbamate (RL648_81), a new KCNQ2/3-specific activator that is .15 times more potent and also more selective than retigabine. We suggest that RL648_81 is a promising clinical candidate for treating or preventing neurologic disorders associated with neuronal hyperexcitability.

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Section: Discussionmentioning

confidence: 85%

Synthesis and Evaluation of Potent KCNQ2/3-Specific Channel Activators

et al. 2016

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“…The Ind amino acid has seen limited use in structure-function studies for hydrogen bond testing (Lacroix et al, 2012; Pless et al, 2013, 2014; Kim et al, 2015; Zhang et al, 2015) and none thus far in structural or computational studies that would inform on its tolerance once encoded within a protein. For instance, it is not known if the Ind substitution would specifically limit hydrogen bonding at the indole nitrogen atom (the purpose for which it was designed) or could it also produce a new side-chain orientation that itself alters protein function.…”

Section: Resultsmentioning

confidence: 99%

Atomic mutagenesis in ion channels with engineered stoichiometry

Lueck

Mackey

Infield

et al. 2016

eLife

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C-type inactivation of potassium channels fine-tunes the electrical signaling in excitable cells through an internal timing mechanism that is mediated by a hydrogen bond network in the channels' selectively filter. Previously, we used nonsense suppression to highlight the role of the conserved Trp434-Asp447 indole hydrogen bond in Shaker potassium channels with a non-hydrogen bonding homologue of tryptophan, Ind (Pless et al., 2013). Here, molecular dynamics simulations indicate that the Trp434Ind hydrogen bonding partner, Asp447, unexpectedly 'flips out' towards the extracellular environment, allowing water to penetrate the space behind the selectivity filter while simultaneously reducing the local negative electrostatic charge. Additionally, a protein engineering approach is presented whereby split intein sequences are flanked by endoplasmic reticulum retention/retrieval motifs (ERret) are incorporated into the N- or C- termini of Shaker monomers or within sodium channels two-domain fragments. This system enabled stoichiometric control of Shaker monomers and the encoding of multiple amino acids within a channel tetramer.DOI: http://dx.doi.org/10.7554/eLife.18976.001

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“…During the past decade, K V 7 agonists have become a target for research seeking to design new therapies for neurological disorders. It was shown that the K V 7 agonist Retigabine, a clinically-used anticonvulsant, shifts the voltage dependence of activation of the heteromeric K V 7.2/K V 7.3 channel to more negative potentials, facilitating activation 66-70 . More recently, the heteromeric K V 7.2/K V 7.3 channel has a strong hysteretic behavior displaying, at least 2 modes, 71 analogs to what it has been discussed above.…”

Section: Introductionmentioning

confidence: 91%

Hysteresis in voltage-gated channels

Villalba-Galea

2016

Channels

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Ion channels constitute a superfamily of membrane proteins found in all living creatures. Their activity allows fast translocation of ions across the plasma membrane down the ion's transmembrane electrochemical gradient, resulting in a difference in electrical potential across the plasma membrane, known as the membrane potential. A group within this superfamily, namely voltage-gated channels, displays activity that is sensitive to the membrane potential. The activity of voltage-gated channels is controlled by the membrane potential, while the membrane potential is changed by these channels' activity. This interplay produces variations in the membrane potential that have evolved into electrical signals in many organisms. These signals are essential for numerous biological processes, including neuronal activity, insulin release, muscle contraction, fertilization and many others. In recent years, the activity of the voltage-gated channels has been observed not to follow a simple relationship with the membrane potential. Instead, it has been shown that the activity of voltage-gated channel displays hysteresis. In fact, a growing number of evidence have demonstrated that the voltage dependence of channel activity is dynamically modulated by activity itself. In spite of the great impact that this property can have on electrical signaling, hysteresis in voltage-gated channels is often overlooked. Addressing this issue, this review provides examples of voltage-gated ion channels displaying hysteretic behavior. Further, this review will discuss how Dynamic Voltage Dependence in voltage-gated channels can have a physiological role in electrical signaling. Furthermore, this review will elaborate on the current thoughts on the mechanism underlying hysteresis in voltage-gated channels.

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Atomic basis for therapeutic activation of neuronal potassium channels

Cited by 71 publications

References 52 publications

Synthesis and Evaluation of Potent KCNQ2/3-Specific Channel Activators

Synthesis and Evaluation of Potent KCNQ2/3-Specific Channel Activators

Atomic mutagenesis in ion channels with engineered stoichiometry

Hysteresis in voltage-gated channels

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