Pharmacogenetics of <scp>KCNQ</scp> channel activation in 2 potassium channelopathy mouse models of epilepsy

Vanhoof-Villalba, Stephanie L.; Gautier, Nicole; Mishra, Vikas; Glasscock, Edward

doi:10.1111/epi.13978

Cited by 15 publications

(7 citation statements)

References 38 publications

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“…The results obtained revealed that injection of either Lv-shGAS5 or Lv-miR-135a-5p significantly prolonged the epileptic latency and reduced the frequency of seizures. Although the implications of KCNQ3 and potassium channels in the pathogenesis of epilepsy have been illustrated in many studies, [35][36][37] the antiepileptic drugs dealing with potassium channels are still under investigated. This study highlighted a novel molecule mechanism that Lv-miR-135a-5p and Lv-shGAS5 are able to inhibit KCNQ3 expression in the rat models of epileptic seizure (Figure 4), indicating that downregulation of lncRNA GAS5 can decrease KCNQ3 through sponging miR-135a-5p to prolong latent period and to reduce seizure frequency.…”

Section: Discussionmentioning

confidence: 99%

Long noncoding RNA GAS5 silencing inhibits the expression of KCNQ3 by sponging miR‐135a‐5p to prevent the progression of epilepsy

Zheng

et al. 2019

The Kaohsiung J of Med Scie

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Epilepsy is one of the most common neurological disorders in humans. Recently, long noncoding RNAs (lncRNAs) have been reported to be important players in neurological diseases. Herein, this study aimed to examine the effect of lncRNA GAS5 on the occurrence of epilepsy in rat and cell models of epileptic seizure. The expression of lncRNA GAS5 was measured in the established rat and cell models. The binding sites between lncRNA GAS5 and miR‐135a‐5p, as well as those between miR‐135a‐5p and 3′ untranslated region of KCNQ3 were predicted by miRDB and Targetscan, separately, followed by verification using dual‐luciferase reporter gene assay. The expression of miR‐135a‐5p was measured in response to the overexpression of lncRNA GAS5. The mRNA and protein levels of KCNQ3 were examined in response to overexpression of miR‐135a‐5p. Next, the latency of epilepsy and frequency of epileptic seizures were assessed in rats injected with Lv‐shGAS5 and Lv‐miR‐135a‐5p in epileptic seizure model. In the rat and cell models, lncRNA GAS5 was highly expressed when epileptic seizure was induced. The expression of miR‐135a‐5p was decreased by overexpression of lncRNA GAS5. Meanwhile, the mRNA and protein levels of KCNQ3 were decreased in response to knockdown of miR‐135a‐5p. After the treatment of Lv‐shGAS5 and Lv‐miR‐135a‐5p, the average latent period of epilepsy was prolonged and the frequency of seizures was decreased. The key findings of the present study provide evidence emphasizing that lncRNA GAS5 functions as a competitive endogenous RNA of miR‐135a‐5p to increase expression of KCNQ3, and lncRNA GAS5 silencing inhibited the occurrence and progression of epilepsy.

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Section: Discussionmentioning

confidence: 99%

Long noncoding RNA GAS5 silencing inhibits the expression of KCNQ3 by sponging miR‐135a‐5p to prevent the progression of epilepsy

Zheng

et al. 2019

The Kaohsiung J of Med Scie

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“…The enhanced activity of these voltage-gated K + channels can generate the macroscopic M-type K + current ( I K(M) ), which is biophysically manifested by current activation in response to low-threshold voltage and, once activated, the current displays a slowly activating and deactivating property [ 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Targeting I K(M) is noticeably viewed as an adjunctive regimen for the management of various neurological or endocrine disorders associated with neuronal over-excitability, which include cognitive dysfunction, neuropathic pain, and epilepsy [ 27 , 28 , 29 , 30 ]. Alternatively, previous studies have demonstrated that KYNA-mediated vasodilation and hypotension could be attributed to the activation of KCNQ channels [ 18 , 31 ].…”

Section: Introductionmentioning

confidence: 99%

Effective Activation by Kynurenic Acid and Its Aminoalkylated Derivatives on M-Type K+ Current

Lin

Fang

et al. 2021

IJMS

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Kynurenic acid (KYNA, 4-oxoquinoline-2-carboxylic acid), an intermediate of the tryptophan metabolism, has been recognized to exert different neuroactive actions; however, the need of how it or its aminoalkylated amide derivative N-(2-(dimethylamino)ethyl)-3-(morpholinomethyl)-4-oxo-1,4-dihydroquinoline-2-carboxamide (KYNA-A4) exerts any effects on ion currents in excitable cells remains largely unmet. In this study, the investigations of how KYNA and other structurally similar KYNA derivatives have any adjustments on different ionic currents in pituitary GH3 cells and hippocampal mHippoE-14 neurons were performed by patch-clamp technique. KYNA or KYNA-A4 increased the amplitude of M-type K+ current (IK(M)) and concomitantly enhanced the activation time course of the current. The EC50 value required for KYNA- or KYNA-A4 -stimulated IK(M) was yielded to be 18.1 or 6.4 μM, respectively. The presence of KYNA or KYNA-A4 shifted the relationship of normalized IK(M)-conductance versus membrane potential to more depolarized potential with no change in the gating charge of the current. The voltage-dependent hysteretic area of IK(M) elicited by long-lasting triangular ramp pulse was observed in GH3 cells and that was increased during exposure to KYNA or KYNA-A4. In cell-attached current recordings, addition of KYNA raised the open probability of M-type K+ channels, along with increased mean open time of the channel. Cell exposure to KYNA or KYNA-A4 mildly inhibited delayed-rectifying K+ current; however, neither erg-mediated K+ current, hyperpolarization-activated cation current, nor voltage-gated Na+ current in GH3 cells was changed by KYNA or KYNA-A4. Under whole-cell, current-clamp recordings, exposure to KYNA or KYNA-A4 diminished the frequency of spontaneous action potentials; moreover, their reduction in firing frequency was attenuated by linopirdine, yet not by iberiotoxin or apamin. In hippocampal mHippoE-14 neurons, the addition of KYNA also increased the IK(M) amplitude effectively. Taken together, the actions presented herein would be one of the noticeable mechanisms through which they modulate functional activities of excitable cells occurring in vivo.

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“…Once being activated, this type of K + currents can be sensitiv block by linopirdine and it is demonstrated to exhibit a slowly activating and deactiva property [46][47][48][49][50][51]. Alternatively, targeting IK(M) has been noticeably viewed as an adju tive regimen for the management of various neurological, smooth muscle, or endoc disorders closely linked to membrane hyperexcitability, which include cognitive dysfu tion, epilepsy, and over-active bladder [47,[52][53][54][55]. However, to our knowledge, how whether this agent can interact directly with KV channels to modify the amplitude gating of voltage-gated K + currents (e.g., M-type K + current) remain largely unknown Therefore, in terms of the considerations stated above, in the current study, we cided to explore the possible perturbations of SOL on IK(M) in pituitary GH3 cells mouse mHippoE-14 hippocampal neurons.…”

Section: Introductionmentioning

confidence: 99%

The Effectiveness in Activating M-Type K+ Current Produced by Solifenacin ([(3R)-1-azabicyclo[2.2.2]octan-3-yl] (1S)-1-phenyl-3,4-dihydro-1H-isoquinoline-2-carboxylate): Independent of Its Antimuscarinic Action

Cho

Chuang

2021

IJMS

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Solifenacin (Vesicare®, SOL), known to be a member of isoquinolines, is a muscarinic antagonist that has anticholinergic effect, and it has been beneficial in treating urinary incontinence and neurogenic detrusor overactivity. However, the information regarding the effects of SOL on membrane ionic currents is largely uncertain, despite its clinically wide use in patients with those disorders. In this study, the whole-cell current recordings revealed that upon membrane depolarization in pituitary GH3 cells, the exposure to SOL concentration-dependently increased the amplitude of M-type K+ current (IK(M)) with effective EC50 value of 0.34 μM. The activation time constant of IK(M) was concurrently shortened in the SOL presence, hence yielding the KD value of 0.55 μM based on minimal reaction scheme. As cells were exposed to SOL, the steady-state activation curve of IK(M) was shifted along the voltage axis to the left with no change in the gating charge of the current. Upon an isosceles-triangular ramp pulse, the hysteretic area of IK(M) was increased by adding SOL. As cells were continually exposed to SOL, further application of acetylcholine (1 μM) failed to modify SOL-stimulated IK(M); however, subsequent addition of thyrotropin releasing hormone (TRH, 1 μM) was able to counteract SOL-induced increase in IK(M) amplitude. In cell-attached single-channel current recordings, bath addition of SOL led to an increase in the activity of M-type K+ (KM) channels with no change in the single channel conductance; the mean open time of the channel became lengthened. In whole-cell current-clamp recordings, the SOL application reduced the firing of action potentials (APs) in GH3 cells; however, either subsequent addition of TRH or linopirdine was able to reverse SOL-mediated decrease in AP firing. In hippocampal mHippoE-14 neurons, the IK(M) was also stimulated by adding SOL. Altogether, findings from this study disclosed for the first time the effectiveness of SOL in interacting with KM channels and hence in stimulating IK(M) in electrically excitable cells, and this noticeable action appears to be independent of its antagonistic activity on the canonical binding to muscarinic receptors expressed in GH3 or mHippoE-14 cells.

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Pharmacogenetics of KCNQ channel activation in 2 potassium channelopathy mouse models of epilepsy

Cited by 15 publications

References 38 publications

Long noncoding RNA GAS5 silencing inhibits the expression of KCNQ3 by sponging miR‐135a‐5p to prevent the progression of epilepsy

Long noncoding RNA GAS5 silencing inhibits the expression of KCNQ3 by sponging miR‐135a‐5p to prevent the progression of epilepsy

Effective Activation by Kynurenic Acid and Its Aminoalkylated Derivatives on M-Type K+ Current

The Effectiveness in Activating M-Type K+ Current Produced by Solifenacin ([(3R)-1-azabicyclo[2.2.2]octan-3-yl] (1S)-1-phenyl-3,4-dihydro-1H-isoquinoline-2-carboxylate): Independent of Its Antimuscarinic Action

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