Suppression of KV7/KCNQ potassium channel enhances neuronal differentiation of PC12 cells

Zhou, Najing; Huang, Sheng Chieh; Li, Li; Huang, Dongyang; Yunli, Yan; Du, Xiaona; Zhang, Hailin

doi:10.1016/j.neuroscience.2016.07.024

Cited by 13 publications

(9 citation statements)

References 41 publications

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“…Culturing PC12 cells for 4–7 days with NGF resulted in extensive neurite outgrowth and increased expression of native voltage-gated potassium currents (Fig. 4c ), as previously reported 27 , 28 . We found that 8/10 PC12 cells studied expressed potassium current sensitive to the KCNQ channel blocker XE991 (10 µM).…”

Section: Resultssupporting

confidence: 86%

“…We next tested the effected of GABA on native M-current in PC12 cells, a rat pheochromocytoma cell line of neural crest origin that retains many of the properties of dopaminergic neurons and has previously been used to study M-current 27 , 28 . Culturing PC12 cells for 4–7 days with NGF resulted in extensive neurite outgrowth and increased expression of native voltage-gated potassium currents (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Direct neurotransmitter activation of voltage-gated potassium channels

2018

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Voltage-gated potassium channels KCNQ2–5 generate the M-current, which controls neuronal excitability. KCNQ2–5 subunits each harbor a high-affinity anticonvulsant drug-binding pocket containing an essential tryptophan (W265 in human KCNQ3) conserved for >500 million years, yet lacking a known physiological function. Here, phylogenetic analysis, electrostatic potential mapping, in silico docking, electrophysiology, and radioligand binding assays reveal that the anticonvulsant binding pocket evolved to accommodate endogenous neurotransmitters including γ-aminobutyric acid (GABA), which directly activates KCNQ5 and KCNQ3 via W265. GABA, and endogenous metabolites β-hydroxybutyric acid (BHB) and γ-amino-β-hydroxybutyric acid (GABOB), competitively and differentially shift the voltage dependence of KCNQ3 activation. Our results uncover a novel paradigm: direct neurotransmitter activation of voltage-gated ion channels, enabling chemosensing of the neurotransmitter/metabolite landscape to regulate channel activity and cellular excitability.

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Section: Resultssupporting

confidence: 86%

Section: Resultsmentioning

confidence: 99%

Direct neurotransmitter activation of voltage-gated potassium channels

2018

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“… 10 As the KCNQ channel opener, retigabine (RTG) induced I M in different types of neurons and inhibited pathological hyperexcitability AP firing in several different experimental conditions. 2 , 3 , 32 – 35 RTG have been suggested to treat nociception modulated by I M and relieved neuropathic pain provoked by stimulation of afferent neurons. 3 , 34 XE991 blocked the KCNQ induced I M and therefore potentiated the hyperexcitability in several different experimental conditions.…”

Section: Introductionmentioning

confidence: 99%

“… 3 , 34 XE991 blocked the KCNQ induced I M and therefore potentiated the hyperexcitability in several different experimental conditions. 3 , 20 , 32 , 33 , 36 , 37 Therefore, we investigated the effects of RTG administration on neuronal excitability in DRG afferent neuronal activities of diabetic neuropathic rats as well as the effects of RTG treatment on pain nociceptive behavior of diabetic neuropathic rats. In addition, the effects of XE991 on neuronal excitability and neuropathic behavior of diabetic neuropathic rats were also evaluated in order to fully investigate the involvement of KCNQ2/3/5 channels in nociceptive sensory transduction of diabetic neuropathic pain.…”

Section: Introductionmentioning

confidence: 99%

KCNQ2/3/5 channels in dorsal root ganglion neurons can be therapeutic targets of neuropathic pain in diabetic rats

Liu

et al. 2018

Mol Pain

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BackgroundDiabetic neuropathic pain is poorly controlled by analgesics, and the precise molecular mechanisms underlying hyperalgesia remain unclear. The KCNQ2/3/5 channels expressed in dorsal root ganglion neurons are important in pain transmission. The expression and activity of KCNQ2/3/5 channels in dorsal root ganglion neurons in rats with diabetic neuropathic pain were investigated in this study.MethodsThe mRNA levels of KCNQ2/3/5 channels were analyzed by real-time polymerase chain reaction. The protein levels of KCNQ2/3/5 channels were evaluated by Western blot assay. KCNQ2/3/5 channel expression in situ in dorsal root ganglion neurons was detected by double fluorescent labeling technique. M current (IM) density and neuronal excitability were determined by whole-cell voltage and current clamp recordings. Mechanical allodynia and thermal hyperalgesia were assessed by von Frey filaments and plantar analgesia tester, respectively.ResultsThe mRNA and protein levels of KCNQ2/3/5 channels significantly decreased, followed by the reduction of IM density and elevation of neuronal excitability of dorsal root ganglion neurons from diabetic rats. Activation of KCNQ channels with retigabine reduced the hyperexcitability and inhibition of KCNQ channels with XE991 enhanced the hyperexcitability. Administration of retigabine alleviated both mechanical allodynia and thermal hyperalgesia, while XE991 augmented both mechanical allodynia and thermal hyperalgesia in diabetic neuropathic pain in rats.ConclusionThe findings elucidate the mechanisms by which downregulation of the expression and reduction of the activity of KCNQ2/3/5 channels in diabetic rat dorsal root ganglion neurons contribute to neuronal hyperexcitability, which results in hyperalgesia. These data provide intriguing evidence that activation of KCNQ2/3/5 channels might be the potential new targets for alleviating diabetic neuropathic pain symptoms.

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“…Different ion channels, such as K + and Na + channels are involved in the neuritogenesis events [50][51] . Never-the-less, different steps of neuritogenesis are largely dependent on Ca 2+ -signaling events and thereby involved different Ca 2+ channels [2][3]7 .…”

Section: Discussionmentioning

confidence: 99%

TRPV2 activation reorganizes actin cytoskeleton, induces neurite initiation and branching by altering cAMP levels

Yadav

Goswami

2019

Preprint

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Understanding of molecules and their role in neurite initiation and/or extension is not only helpful to prevent different neurodegenerative diseases but also can be important by which neuronal damages can be repaired. In this work we explored the role of TRPV2, a non-selective cation channel in the context of neurite functions. Using western blot, immunofluorescence, and live cell Ca 2+ -imaging;we confirm that functional TRPV2 is endogenously present in the F11 cell, a model system mimicking peripheral neuron. In F11 cells TRPV2 localizes in specific sub-cellular regions enriched with filamentous actin, such as in growth cone, filopodia, lamellipodia and in neurites. TRPV2 regulates actin cytoskeleton and also interacts with soluble actin. Ectopic expression of TRPV2-GFP but not GFP-only in F11 cell induces more primary and secondary neurites, confirming its role in neurite initiation, extension and branching events. TRPV2-mediated neuritogenesis is dependent on wild-type TRPV2 as cells expressing TRPV2 mutants reveal no neuritogenesis. However, TRPV2-mediated neuritogenesis is unperturbed by the chelation of intracellular Ca 2+ by BAPTA-AM, and thus involves Ca 2+ -independent signaling events also. We demonstrate that pharmacological modulation of TRPV2 alters cellular cAMP levels. These findings are relevant to understand the sprouting of new neurites, neuroregeneration and neuronal plasticity at the cellular, subcellular and molecular level. Such understanding may have border implication in neurodegeneration and peripheral neuropathy.

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Suppression of KV7/KCNQ potassium channel enhances neuronal differentiation of PC12 cells

Cited by 13 publications

References 41 publications

Direct neurotransmitter activation of voltage-gated potassium channels

Direct neurotransmitter activation of voltage-gated potassium channels

KCNQ2/3/5 channels in dorsal root ganglion neurons can be therapeutic targets of neuropathic pain in diabetic rats

TRPV2 activation reorganizes actin cytoskeleton, induces neurite initiation and branching by altering cAMP levels

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