Protein arginine methylation facilitates KCNQ channel-PIP2 interaction leading to seizure suppression

Kim, Hyun Ji; Jeong, Minwoo; Kim, Kyung Ran; Jung, Chang Yun; Lee, Seul Yi; Kim, Hanna; Koh, Jewoo; Vuong, Tuan Anh; Jung, Sang Yong; Yang, Han-Chul; Park, Su Kyung; Choi, Dahee; Kim, Sung Hun; Kang, Kook Hee; Sohn, Jong Woo; Park, Joo Min; Jeon, Daejong; Koo, Seung Hoi; Ho, Won Kyung; Kang, Jong Sun; Kim, Seong-Tae; Cho, Hanna

doi:10.7554/elife.17159

Cited by 37 publications

(35 citation statements)

References 66 publications

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“…In vitro experiments identified 4 modified arginine residues, R333, R345, R353, and R435, on KCNQ2 that also reside in the PIP2-binding region. These modifications require PRMT1 but do not appear to need its close relative PRMT8 122 . PIP2 could not fully rescue M-currents in neurons of PRMT1 heterozygous mice; this points to the involvement or redundancy of other PRMTs.…”

Section: Inflammationmentioning

confidence: 91%

“…Dysregulation of the KCNQ genes is one underlying cause of epilepsy. In a mouse model, PRMT1 heterozygotes have impulsive seizures and their brains feature lower expression of asymmetrically dimethylated KCNQ2 relative to wild types 122 . Further, methylated KCNQ had higher affinity for their binding partner phosphatidylinositol-4,5-bisphosphate (PIP2).…”

Section: Inflammationmentioning

confidence: 99%

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Chemical probes targeting epigenetic proteins: Applications beyond oncology

Ackloo

Brown

Müller³

2017

Epigenetics

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Epigenetic chemical probes are potent, cell-active, small molecule inhibitors or antagonists of specific domains in a protein; they have been indispensable for studying bromodomains and protein methyltransferases. The Structural Genomics Consortium (SGC), comprising scientists from academic and pharmaceutical laboratories, has generated most of the current epigenetic chemical probes. Moreover, the SGC has shared about 4 thousand aliquots of these probes, which have been used primarily for phenotypic profiling or to validate targets in cell lines or primary patient samples cultured in vitro. Epigenetic chemical probes have been critical tools in oncology research and have uncovered mechanistic insights into well-established targets, as well as identify new therapeutic starting points. Indeed, the literature primarily links epigenetic proteins to oncology, but applications in inflammation, viral, metabolic and neurodegenerative diseases are now being reported. We summarize the literature of these emerging applications and provide examples where existing probes might be used.

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Section: Inflammationmentioning

confidence: 91%

Section: Inflammationmentioning

confidence: 99%

Chemical probes targeting epigenetic proteins: Applications beyond oncology

Ackloo

Brown

Müller³

2017

Epigenetics

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“…While phosphorylation of Kv7 subunits is typically associated with channel suppression, phosphorylation of Kv7-bound CaM by protein kinase CK2 has been shown to facilitate CaM interaction with the channel, increasing PIP 2 efficacy and increasing channel amplitude while remaining sensitive to increases in intracellular Ca 2+ [43,134]. Another signaling pathway known to augment the M-current (specifically, channels containing Kv7.2/4/5 subunits) is through the increase in an intracellular reactive oxygen species, ROS [135,136]. It has been shown that the oxidation of three cysteine residues lying within the S2–S3 linker increase the P o of Kv7 channels [135].…”

Section: Kv7 Channel Augmentationmentioning

confidence: 99%

“…It has been shown that the oxidation of three cysteine residues lying within the S2–S3 linker increase the P o of Kv7 channels [135]. Another recently identified pathway for ROS induced augmentation is methylation of arginine residues of Kv7.2 subunit by arginine methyltransferase 1 (Prmt1), which promotes Kv7.2 interaction with PIP 2 [136]. This study also suggests that partial methylation of arginine residues in Kv7 channels is essential for maintaining basal M-current [136].…”

Section: Kv7 Channel Augmentationmentioning

confidence: 99%

Modulation of Kv7 channels and excitability in the brain

Greene

Hoshi

2016

Cell. Mol. Life Sci.

137

152

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Neuronal Kv7 channels underlie a voltage-gated non-inactivating potassium current known as the M-current. Due to its particular characteristics, Kv7 channels show pronounced control over the excitability of neurons. We will discuss various factors that have been shown to drastically alter the activity of this channel such as protein and phospholipid interactions, phosphorylation, calcium, and numerous neurotransmitters. Kv7 channels locate to key areas for the control of action potential initiation and propagation. Moreover, we will explore the dynamic surface expression of the channel modulated by neurotransmitters and neural activity. We will also focus on known principle functions of neural Kv7 channels: control of resting membrane potential and spiking threshold, setting the firing frequency, afterhyperpolarization after burst firing, theta resonance, and transient hyperexcitability from neurotransmitter-induced suppression of the M-current. Finally, we will discuss the contribution of altered Kv7 activity to pathologies such as epilepsy and cognitive deficits.

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“…Recently we and others reported augmentation of KCNQ channel activity via the oxidative modification of a triple-cysteine pocket in the channel S2-S3 linker (11,24,32). Because zinc can bind to cysteines and form redox-sensitive molecular switches (33), we tested if the effect of zinc on KCNQ channels is also redox dependent and mediated by the triple-cysteine pocket.…”

Section: +mentioning

confidence: 99%

Intracellular zinc activates KCNQ channels by reducing their dependence on phosphatidylinositol 4,5-bisphosphate

Gao

Boillat

Huang

et al. 2017

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

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M-type (Kv7, KCNQ) potassium channels are proteins that control the excitability of neurons and muscle cells. Many physiological and pathological mechanisms of excitation operate via the suppression of M channel activity or expression. Conversely, pharmacological augmentation of M channel activity is a recognized strategy for the treatment of hyperexcitability disorders such as pain and epilepsy. However, physiological mechanisms resulting in M channel potentiation are rare. Here we report that intracellular free zinc directly and reversibly augments the activity of recombinant and native M channels. This effect is mechanistically distinct from the known redoxdependent KCNQ channel potentiation. Interestingly, the effect of zinc cannot be attributed to a single histidine-or cysteine-containing zinc-binding site within KCNQ channels. Instead, zinc dramatically reduces KCNQ channel dependence on its obligatory physiological activator, phosphatidylinositol 4,5-bisphosphate (PIP 2 ). We hypothesize that zinc facilitates interactions of the lipid-facing interface of a KCNQ protein with the inner leaflet of the plasma membrane in a way similar to that promoted by PIP 2 . Because zinc is increasingly recognized as a ubiquitous intracellular second messenger, this discovery might represent a hitherto unknown native pathway of M channel modulation and provide a fresh strategy for the design of M channel activators for therapeutic purposes.+ channels are a family of voltagegated K + channels with a very distinctive and robust role in the control of cellular excitability. The channels give rise to noninactivating K + currents with slow kinetics and a very negative activation threshold (−60 mV or even more negative). In combination, these features allow KCNQ channels to remain partially active at voltages near the resting membrane potential of a neuron or a muscle cell and thus strongly influence excitability (1, 2). Transient KCNQ channel inhibition leads to reversible increases in neuronal excitability, whereas long-term losses of KCNQ channel activity often result in debilitating excitability disorders (1, 2). Thus, loss-of-function mutations within KCNQ genes underlie some types of epilepsy, deafness, and arrhythmias, whereas transcriptional down-regulation in sensory nerves may result in chronic pain (2). Conversely, M channel enhancers ("openers") reduce excitability and are clinically used as antiepileptic drugs (e.g., retigabine) or analgesics (e.g., flupirtine) (3). The therapeutic utility of KCNQ channel openers extends to other disorders linked to deregulated excitability, such as anxiety, stroke, and smooth muscle disorders (2, 3); therefore a global quest for specific and selective KCNQ openers is currently underway (3).The KCNQ channel family contains five members, KCNQ1-5 (Kv7.1-Kv7.5). KCNQ1 is expressed mostly within the cardiovascular system, whereas the other members are predominantly neuronal (1, 2). The most abundant M-type channel within the nervous system is believed to be the heteromeric KCNQ2/3 chan...

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Protein arginine methylation facilitates KCNQ channel-PIP2 interaction leading to seizure suppression

Cited by 37 publications

References 66 publications

Chemical probes targeting epigenetic proteins: Applications beyond oncology

Chemical probes targeting epigenetic proteins: Applications beyond oncology

Modulation of Kv7 channels and excitability in the brain

Intracellular zinc activates KCNQ channels by reducing their dependence on phosphatidylinositol 4,5-bisphosphate

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