Neuronal potassium channel openers in the management of epilepsy: role and potential of retigabine

Barrese, Vincenzo; Miceli, Francesco; Soldovieri, Maria Virginia; Ambrosino, Paolo; Iannotti, Fabio Arturo; Cilio, Maria Roberta; Taglialatela, Maurizio

doi:10.2147/cpaa.s15369

Cited by 23 publications

(29 citation statements)

References 90 publications

(106 reference statements)

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“…eel-1 (lf) mutants also have increased electroshock sensitivity consistent with reduced GABAergic transmission (Figure 5D). This defect is suppressed by the anticonvulsant RTG, an agonist for KCNQ2/3 voltage-gated potassium channels in mice and flies (Barrese et al, 2010). While it is unclear how RTG rescues eel-1 mutants, one possibility is RTG relieves hyperexcitation in eel-1 mutants by stimulating potassium channels.…”

Section: Discussionmentioning

confidence: 99%

The HECT Family Ubiquitin Ligase EEL-1 Regulates Neuronal Function and Development

et al. 2017

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Summary Genetic changes in the HECT ubiquitin ligase HUWE1 are associated with intellectual disability, but it remains unknown whether HUWE1 functions in post-mitotic neurons to affect circuit function. Using genetics, pharmacology and electrophysiology, we show that EEL-1, the HUWE1 ortholog in C. elegans, preferentially regulates GABAergic presynaptic transmission. Decreasing or increasing EEL-1 function alters GABAergic transmission and excitatory/inhibitory (E/I) balance in the worm motor circuit, which leads to impaired locomotion and increased sensitivity to electroshock. Furthermore, multiple mutations associated with intellectual disability impair EEL-1 function. While synaptic transmission defects did not result from abnormal synapse formation, sensitizing genetic backgrounds revealed that EEL-1 functions in the same pathway as the RING family ubiquitin ligase RPM-1 to regulate synapse formation and axon termination. These findings from a simple model circuit provide insight into the molecular mechanisms required to obtain E/I balance, and could have implications for the link between HUWE1 and intellectual disability.

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Section: Discussionmentioning

confidence: 99%

The HECT Family Ubiquitin Ligase EEL-1 Regulates Neuronal Function and Development

et al. 2017

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“…Hence, they are subject to a wide range of regulatory pathways 3; 4; 6 , have been identified as molecules in which misfunction underlies a variety of disorders in the cardiovascular, hearing, vestibular, and nervous systems 2; 14; 15 , and are attractive targets for a range of hyperexcitability disorders 11; 12; 13; 14 . Calmodulin (CaM) is a key regulator and affects the function of all Kv7 subtypes through interactions made in both its apo- and calcium-bound forms with the C-terminal tail of the channel 19; 20; 21; 29; 31; 32 .…”

Section: Discussionmentioning

confidence: 99%

“…Consequently, a variety of signaling pathways tune electrical excitability by regulating Kv7 function 3; 4; 6 . Commensurate with their pivotal role in controlling excitation, Kv7 channels are targets for the development of modulators to treat diseases involving neuronal hyperexcitability such as epilepsy and neuropathic pain 11; 12; 13; 14 . Further, mutations in Kv7 channels have been linked to various human diseases, including cardiac arrhythmias, deafness, and epilepsy 2; 14; 15 .…”

Section: Introductionmentioning

confidence: 99%

Structure of a Ca2+/CaM:Kv7.4 (KCNQ4) B-Helix Complex Provides Insight into M Current Modulation

Chang

Tolia

et al. 2013

Journal of Molecular Biology

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Calmodulin (CaM) is an important regulator of Kv7.x (KCNQx) voltage-gated potassium channels. Channels from this family produce neuronal M-currents and cardiac and auditory IKS currents, and harbor mutations that cause arrhythmias, epilepsy, and deafness. Despite extensive functional characterization, biochemical and structural details of the interaction between CaM and the channel have remained elusive. Here, we show that both apo-CaM and Ca2+/CaM bind to the C-terminal tail of the neuronal channel Kv7.4 (KCNQ4), which is involved both hearing and mechanosensation. Interactions between apo-CaM and the Kv7.4 tail involve two C-terminal tail segments, known as the A and B segments, whereas the interaction between Ca2+/CaM and the Kv7.4 C-terminal tail requires only the B segment. Biochemical studies show that the calcium dependence of the CaM:B segment interaction is conserved in all Kv7 subtypes. X-ray crystallographic determination of the structure of the Ca2+/CaM:Kv7.4 B segment complex shows that Ca2+/CaM wraps around the Kv7.4 B segment, which forms an α-helix, in an antiparallel orientation that embodies a variation of the classic 1-14 Ca2+/CaM interaction motif. Taken together with the context of prior studies, our data suggest a model for modulation of neuronal Kv7 channels involving a calcium-dependent conformational switch from an apo-CaM form that bridges the A and B segments to a Ca2+/CaM form bound to the B-helix. The structure presented here also provides a context for a number of disease causing mutations and for further dissection of the mechanisms by which CaM controls Kv7 function.

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“…We hypothesize this is due to the increased seizure threshold for N2. The main target of Retigabine in mammals is a voltage-gated potassium channel, KCNQ2/3 (Barrese et al 2010; Friedman et al 2015; Rundfeldt 1997). The C. elegans ortholog of is kqt-1/2/3; therefore, it is possible that this drug works in a similar mechanism.…”

Section: Discussionmentioning

confidence: 99%

egl-4 modulates electroconvulsive seizure duration in C. elegans

et al. 2018

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Increased neuronal excitability causes seizures with debilitating symptoms. Effective and noninvasive treatments are limited for easing symptoms, partially due to the complexity of the disorder and lack of knowledge of specific molecular faults. An unexplored, novel target for seizure therapeutics is the cGMP/protein kinase G (PKG) pathway, which targets downstream K+ channels, a mechanism similar to Retigabine, a recently FDA-approved antiepileptic drug. Our results demonstrate that increased PKG activity decreased seizure duration in C. elegans utilizing a recently developed electroconvulsive seizure assay. While the fly is a well-established seizure model, C. elegans are an ideal yet unexploited model which easily uptakes drugs and can be utilized for high-throughput screens. In this study, we show that treating the worms with either a potassium channel opener, Retigabine or published pharmaceuticals that increase PKG activity, significantly reduces seizure recovery times. Our results suggest that PKG signaling modulates downstream K+ channel conductance to control seizure recovery time in C. elegans. Hence, we provide powerful evidence, suggesting that pharmacological manipulation of the PKG signaling cascade may control seizure duration across phyla.

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Neuronal potassium channel openers in the management of epilepsy: role and potential of retigabine

Cited by 23 publications

References 90 publications

The HECT Family Ubiquitin Ligase EEL-1 Regulates Neuronal Function and Development

The HECT Family Ubiquitin Ligase EEL-1 Regulates Neuronal Function and Development

Structure of a Ca2+/CaM:Kv7.4 (KCNQ4) B-Helix Complex Provides Insight into M Current Modulation

egl-4 modulates electroconvulsive seizure duration in C. elegans

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