Transient Potassium Channels: Therapeutic Targets for Brain Disorders

Noh, Wonjun; Pak, Sojeong; Choi, Gyeong Man; Yang, Sungchil; Yang, Sunggu

doi:10.3389/fncel.2019.00265

Cited by 42 publications

(39 citation statements)

References 129 publications

(155 reference statements)

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“…Our observations are consistent with findings of the effects of SK3 channel agonists in intact animals [31,38,47,48]. In conditionally SK3-deficient mice, baseline levels of striatal extracellular dopamine are increased [31] while both CyPPA spontaneous firing rate and dopamine release are decreased [49].…”

Section: Plos Onesupporting

confidence: 91%

“…Dopamine neuron susceptibility to excitotoxic injury is potentially relevant to a number of pathological conditions, and therefore so is the development of potential neuroprotective strategies, including the use of pharmacological modulators of SK3 channel function [ 31 – 34 ]. We previously showed that 1-EBIO effectively protects DN in primary cultures of ventral mesencephalon against AMPA-mediated toxicity by sustaining SK3 channel conductance [ 3 ].…”

Section: Discussionmentioning

confidence: 99%

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Age-dependent neuroprotective effect of an SK3 channel agonist on excitotoxity to dopaminergic neurons in organotypic culture

Maldonado¹,

Jenkins

Belálcazar

et al. 2020

PLoS ONE

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Background Small conductance, calcium-activated (SK3) potassium channels control the intrinsic excitability of dopaminergic neurons (DN) in the midbrain and modulate their susceptibility to toxic insults during development. Methods We evaluated the age-dependency of the neuroprotective effect of an SK3 agonist, 1-Ethyl-1,3-dihydro-2H-benzimidazol-2-one (1-EBIO), on Amino-3-hydroxy-5-methylisoxazole-4propionic acid (AMPA) excitotoxicity to DN in ventral mesencephalon (VM) organotypic cultures. Results Most tyrosine hydroxylase (TH)+ neurons were also SK3+; SK3+/TH-cells (DN+) were common at each developmental stage but more prominently at day in vitro (DIV) 8. Young DN+ neurons were small bipolar and fusiform, whereas mature ones were large and multipolar. Exposure of organotypic cultures to AMPA (100 μm, 16 h) had no effect on the survival of DN+ at DIV 8, but caused significant toxicity at DIV 15 (n = 15, p = 0.005) and DIV 22 (n = 15, p<0.001). These results indicate that susceptibility of DN to AMPA excitotoxicity is developmental stage-dependent in embryonic VM organotypic cultures. Immature DN+ (small, bipolar) were increased after AMPA (100 μm, 16 h) at DIV 8, at the expense of the number of differentiated (large, multipolar) DN+ (p = 0.039). This effect was larger at DIV 15 (p<<<0.0001) and at DIV 22 (p<<<0.0001). At DIV 8, 30 μM 1-EBIO resulted in a large increase in DN+. At DIV 15, AMPA toxicity was prevented by exposure to 30 μM, but not

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Section: Plos Onesupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Age-dependent neuroprotective effect of an SK3 channel agonist on excitotoxity to dopaminergic neurons in organotypic culture

Maldonado¹,

Jenkins

Belálcazar

et al. 2020

PLoS ONE

View full text Add to dashboard Cite

show abstract

“…Dopamine neuron susceptibility to excitotoxic injury is potentially relevant to a number of pathological conditions, and therefore so is the development of potential neuroprotective strategies, including the use of pharmacological modulators of SK3. channel function (Noh et al, 2019). We previously showed that 1-EBIO effectively protects DN in primary cultures of ventral mesencephalon against AMPA-mediated toxicity by sustaining SK3.…”

Section: Discussionmentioning

confidence: 98%

Age-dependent neuroprotective effect of an SK3. channel agonist on excitotoxity to dopaminergic neurons in organotypic culture

Maldonado

Jenkins

Belálcazar³

et al. 2019

Preprint

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calcium-activated potassium channel 3 also known as K Ca 2.3; DIV: days in vitro; DN: dopaminergic neurons. AbstractWe evaluated the age-dependency of the neuroprotective effect of an small-conductance calcium activated potassium channel 3 (SK3) agonist, 1-EBIO, on AMPA excitoxicity to dopaminergic neurons (DN) in organotypic cultures. Most TH+ neurons were also SK3+. SK3+/TH-cells (DN+) were common at each developmental stage but more prominently at day in vitro (DIV) 8. Young DN+ neurons were small bipolar and fusiform, whereas mature ones were large and multipolar. Exposure of organotypic cultures to AMPA (100 μm, 16 h) had no effect on the survival of DN+ at DIV 8, but caused significant toxicity at DIV 15 (n=15, p=0.005) and DIV 22 (n=15, p<<0.001). These results indicate that susceptibility of DN to AMPA excitotoxicity is developmental stage-dependent in embryonic VM organotypic cultures. Immature DN+ (small, bipolar) were increased after AMPA (100 μm, 16 h) at DIV 8, at the expense of the number of differentiated (large, multipolar) DN+ (p=0.039). This effect was larger at DIV 15 (p<<<0.0001) and at DIV 22 (p<<<0.0001). At DIV 8, 30 μM 1-EBIO resulted in a large increase in DN+. At DIV 15, AMPA toxicity was prevented by exposure to 30 μM, but not 100 μM 1-EBIO. At DIV 22, excitotoxicity was unaffected by 30 μM 1-EBIO, and partially reduced by 100 μM 1-EBIO. The effects of the SK3. channel agonist 1-EBIO on the survival of SK3.-expressing dopaminergic neurons were concentrationdependent and influenced by neuronal developmental stage.

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“…It controls the threshold for action potentials and repetitive firing in visual cortical pyramidal neurons (Yuan, Burkhalter, & Nerbonne, ), and it is critically required for the suppression of excitability in granule cells during their maturation (Shibata et al, ). I A channels and Ca 2+ ‐permeable channels (such as NMDARs) play counteracting roles in regulating neuronal excitability (Noh, Pak, Choi, Yang, & Yang, ). Furthermore, enhanced excitatory input can also negatively regulate neuronal excitability via up‐regulating the I A density (Shen et al, ).…”

Section: Discussionmentioning

confidence: 99%

Down‐regulation of miR‐3068‐3p enhances kcnip4‐regulated A‐type potassium current to protect against glutamate‐induced excitotoxicity

Wang

Zhou

et al. 2019

Journal of Neurochemistry

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The main cause of excitotoxic neuronal death in ischemic stroke is the massive release of glutamate. Recently, microRNAs (miRNAs) have been found to play an essential role in stroke pathology, although the molecular mechanisms remain to be investigated. Here, to identify potential candidate miRNAs involved in excitotoxicity, we treated rat primary cortical neurons with glutamate and found that miR‐3068‐3p, a novel miRNA, was up‐regulated. We hypothesized that restoring miR‐3068‐3p expression might influence the neuronal injury outcomes. The inhibition of miR‐3068‐3p, using tough decoy lentiviruses, significantly attenuated the effects of glutamate on neuronal viability and intracellular calcium overload. To unravel the mechanisms, we employed bioinformatics analysis and RNA sequencing to identify downstream target genes. Additional luciferase assays and western blots validated kcnip4, a Kv4‐mediated A‐type potassium current (IA) regulator, as a direct target of miR‐3068‐3p. The inhibition of miR‐3068‐3p increased kcnip4 expression and vice versa. In addition, the knockdown of kcnip4 by shRNA abolished the protective effect of miR‐3068‐3p, and over‐expressing kcnip4 alone was sufficient to play a neuroprotective role in excitotoxicity. Moreover the inhibition of miR‐3068‐3p enhanced the IA density, and the pharmacological inhibition of IA abrogated the protective role of miR‐3068‐3p inhibition and kcnip4 over‐expression. Therefore, we conclude that inhibition of miR‐3068‐3p protects against excitotoxicity via its target gene, kcnip4, and kcnip4‐regulated IA. Our data suggest that the miR‐3068‐3p/kcnip4 axis may serve as a novel target for the treatment of ischemic stroke.

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Transient Potassium Channels: Therapeutic Targets for Brain Disorders

Cited by 42 publications

References 129 publications

Age-dependent neuroprotective effect of an SK3 channel agonist on excitotoxity to dopaminergic neurons in organotypic culture

Age-dependent neuroprotective effect of an SK3 channel agonist on excitotoxity to dopaminergic neurons in organotypic culture

Age-dependent neuroprotective effect of an SK3. channel agonist on excitotoxity to dopaminergic neurons in organotypic culture

Down‐regulation of miR‐3068‐3p enhances kcnip4‐regulated A‐type potassium current to protect against glutamate‐induced excitotoxicity

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