Epilepsy-Related Slack Channel Mutants Lead to Channel Over-Activity by Two Different Mechanisms

Tang, Qiong-Yao; Zhang, Feifei; Xu, Jie; Wang, Ran; Chen, Jian; Logothetis, Diomedes E.; Zhang, Zhe

doi:10.1016/j.celrep.2015.12.019

Cited by 72 publications

(94 citation statements)

References 54 publications

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“…We suggest that the normal suppression of Slack currents by its interaction with Phactr1 may be reduced or missing in human mutant Slack channels that produce early onset epilepsy and intellectual disability. This is consistent with three findings: (i) most of disease-causing mutations are gain-of-function channel mutations that increase potassium current, 6,7,11,17 (but see reference 19), (ii) some of these mutations have been found to act as if they are constitutively phosphorylated, 11 and (iii) Slack-Phactr1 interactions have been found to be abnormal in these mutations. 4 Thus, the Slack-Phactr1 interaction may represent a target for developing novel therapeutics toward these devastating diseases.…”

Section: Discussionsupporting

confidence: 88%

Phactr1 regulates Slack (KCNT1) channels via protein phosphatase 1 (PP1)

et al. 2019

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The Slack (KCNT1) gene encodes sodium‐activated potassium channels that are abundantly expressed in the central nervous system. Human mutations alter the function of Slack channels, resulting in epilepsy and intellectual disability. Most of the disease‐causing mutations are located in the extended cytoplasmic C‐terminus of Slack channels and result in increased Slack current. Previous experiments have shown that the C‐terminus of Slack channels binds a number of cytoplasmic signaling proteins. One of these is Phactr1, an actin‐binding protein that recruits protein phosphatase 1 (PP1) to certain phosphoprotein substrates. Using co‐immunoprecipitation, we found that Phactr1 is required to link the channels to actin. Using patch clamp recordings, we found that co‐expression of Phactr1 with wild‐type Slack channels reduces the current amplitude but has no effect on Slack channels in which a conserved PKC phosphorylation site (S407) that regulates the current amplitude has been mutated. Furthermore, a Phactr1 mutant that disrupts the binding of PP1 but not that of actin fails to alter Slack currents. Our data suggest that Phactr1 regulates the Slack by linking PP1 to the channel. Targeting Slack‐Phactr1 interactions may therefore be helpful in developing the novel therapies for brain disorders associated with the malfunction of Slack channels.

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Section: Discussionsupporting

confidence: 88%

Phactr1 regulates Slack (KCNT1) channels via protein phosphatase 1 (PP1)

et al. 2019

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“…Epilepsy-related mutant forms of the Slack channel feature enhanced channel activity 17,30–32 . Analogously, the H159Y mutant form of C. elegans SLO-2 isolated in this study featured higher channel activity (Fig.…”

Section: Resultsmentioning

confidence: 99%

SLO potassium channels antagonize premature decision making in C. elegans

et al. 2018

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Animals must modify their behavior with appropriate timing to respond to environmental changes. Yet, the molecular and neural mechanisms regulating the timing of behavioral transition remain largely unknown. By performing forward genetics to reveal mechanisms that underlie the plasticity of thermotaxis behavior in C. elegans, we demonstrated that SLO potassium channels and a cyclic nucleotide-gated channel, CNG-3, determine the timing of transition of temperature preference after a shift in cultivation temperature. We further revealed that SLO and CNG-3 channels act in thermosensory neurons and decelerate alteration in the responsiveness of these neurons, which occurs prior to the preference transition after a temperature shift. Our results suggest that regulation of sensory adaptation is a major determinant of latency before animals make decisions to change their behavior.

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“…Studies characterizing other epilepsy-linked Slack mutations have commonly used Xenopus oocytes. A recent report by Tang et al (2016) studied F932(911)I expression in Xenopus oocytes and report that the mutation slightly increases sodium sensitivity. It is possible that the different cellular environments provided by the oocyte and CHO expression systems are responsible for this inconsistency.…”

Section: Discussionmentioning

confidence: 99%

The Phe932Ile mutation in KCNT1 channels associated with severe epilepsy, delayed myelination and leukoencephalopathy produces a loss-of-function channel phenotype

2017

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Sodium-activated potassium (KNa) channels contribute to firing frequency adaptation and slow afterhyperpolarization. The KCNT1 gene (also known as SLACK) encodes a KNa subunit that is expressed throughout the central and peripheral nervous systems. Missense mutations of the SLACK C-terminus have been reported in several patients with rare forms of early onset epilepsy and in some cases severely delayed myelination. To date, such mutations identified in patients with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), epilepsy of infancy with migrating focal seizures (EIMFS) and Otahara syndrome (OS) have been reported to be gain-of-function mutations (Villa & Combi, 2016). An exome sequencing study identified a p.Phe932Ile KCNT1 mutation as the disease-causing change in a child with severe early infantile epileptic encephalopathy and abnormal myelination (Vanderver et al., 2014). We characterized an analogous mutation in the rat Slack channel and unexpectedly found this mutation to produce a loss-of-function phenotype. In an effort to restore current, we tested the known Slack channel opener loxapine. Loxapine exhibited no effect, indicating that this mutation either caused the channel to be insensitive to this established opener or proper translation and trafficking to the membrane was disrupted. Protein analysis confirmed that while total mutant protein did not differ from wild type, membrane expression of the mutant channel was substantially reduced. Although gain-of-function mutations to the Slack channel are linked to epileptic phenotypes, this is the first reported loss-of-function mutation linked to severe epilepsy and delayed myelination.

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Epilepsy-Related Slack Channel Mutants Lead to Channel Over-Activity by Two Different Mechanisms

Cited by 72 publications

References 54 publications

Phactr1 regulates Slack (KCNT1) channels via protein phosphatase 1 (PP1)

Phactr1 regulates Slack (KCNT1) channels via protein phosphatase 1 (PP1)

SLO potassium channels antagonize premature decision making in C. elegans

The Phe932Ile mutation in KCNT1 channels associated with severe epilepsy, delayed myelination and leukoencephalopathy produces a loss-of-function channel phenotype

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