GIRK1-mediated inwardly rectifying potassium current suppresses the epileptiform burst activities and the potential antiepileptic effect of ML297

Huang, Yian; Zhang, Yuwen; Kong, Sue; Zang, Kai; Jiang, Shize; Wan, Li; Chen, Lulan; Wang, Guoxiang; Jiang, Min; Wang, Xin; Hu, Jie; Wang, Yun

doi:10.1016/j.biopha.2018.02.114

Cited by 24 publications

(21 citation statements)

References 49 publications

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“…Alterations in the function of this potassium channel subunit have been associated with epilepsy. 14 It remains unclear how these variants of NR4A2 contribute to the epileptogenesis. However, the physiologic role of NR4A2 provides a clue toward the complex phenotypes of the patients with variants in this gene.…”

Section: Discussionmentioning

confidence: 99%

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De novo variants of NR4A2 are associated with neurodevelopmental disorder and epilepsy

Singh

Gupta

Zech

et al. 2020

Genetics in Medicine

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This study characterizes the clinical and genetic features of nine unrelated patients with de novo variants in the NR4A2 gene. Methods: Variants were identified and de novo origins were confirmed through trio exome sequencing in all but one patient. Targeted RNA sequencing was performed for one variant to confirm its splicing effect. Independent discoveries were shared through GeneMatcher. Results: Missense and loss-of-function variants in NR4A2 were identified in patients from eight unrelated families. One patient carried a larger deletion including adjacent genes. The cases presented with developmental delay, hypotonia (six cases), and epilepsy (six cases). De novo status was confirmed for eight patients. One variant was demonstrated to affect splicing and result in expression of abnormal transcripts likely subject to nonsensemediated decay. Conclusion: Our study underscores the importance of NR4A2 as a disease gene for neurodevelopmental disorders and epilepsy. The identified variants are likely causative of the seizures and additional developmental phenotypes in these patients.

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Section: Discussionmentioning

confidence: 99%

“…Alterations in the function of this potassium channel subunit have been associated with epilepsy. 14 …”

Section: Discussionmentioning

confidence: 99%

De novo variants of NR4A2 are associated with neurodevelopmental disorder and epilepsy

Singh

Gupta

Zech

et al. 2020

Genetics in Medicine

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“…ML297's effects on GIRK channels expressed in other types of neurons, particularly cortical neurons, would also greatly contribute to its sleep-promoting action. In addition, ML297 has shown anticonvulsant activity in mice induced by either pentylenetetrazole or electric shock [24,56], and anxiolytic effects on anxiety-like behavior in mice [40].…”

Section: Discussionmentioning

confidence: 99%

Direct activation of G-protein-gated inward rectifying K+ channels promotes nonrapid eye movement sleep

Zou

Cao

Guan

et al. 2018

Sleep

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Study Objectives: A major challenge in treating insomnia is to find effective medicines with fewer side effects. Activation of G-protein-gated inward rectifying K + channels (GIRKs) by GABA B agonists baclofen or γ-hydroxybutyric acid (GHB) promotes nonrapid eye movement (NREM) sleep and consolidates sleep. However, baclofen has poor brain penetration, GHB possesses abuse liability, and in rodents both drugs cause spike-wave discharges (SWDs), an absence seizure activity. We tested the hypothesis that direct GIRK activation promotes sleep without inducing SWD using ML297, a potent and selective GIRK activator. Methods: Whole-cell patch-clamp recordings from hypocretin/orexin or hippocampal neurons in mouse brain slices were made to study neuronal excitability and synaptic activity; spontaneous activity, locomotion, contextual and tone-conditioned memory, and novel object recognition were assessed. Electroencephalogram/ electromyogram (EEG/EMG) recordings were used to study GIRK modulation of sleep. Results: ML297, like baclofen, caused membrane hyperpolarization, decreased input resistance, and blockade of spontaneous action potentials. Unlike baclofen, ML297 (5-10 µM) did not cause significant depression of postsynaptic excitatory and inhibitory currents (EPSCs-IPSCs), indicating preferential postsynaptic inhibition. ML297 (30 mg/kg, i.p.) inhibited wake activity and locomotion, and preferentially increased NREM sleep without altering EEG delta power, REM sleep, inducing SWDs, or impairing conditioned memory and novel object recognition. Conclusions: This study finds that direct activation of neuronal GIRK channels modulates postsynaptic membrane excitability and prolongs NREM sleep without changing sleep intensity, inducing SWDs, or impairing memory in rodents. These results suggest that direct GIRK activation with a selective compound may present an innovative approach for the treatment of chronic insomnia.

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“…Selective activation of GIRK channels by ML297 requires two amino acids specific to the GIRK subunit [ 8 ]. Systemic application of ML297 has been reported to be associated with anxiolytic [ 8 ] and antiepileptic [ 9 ] effects in mice. However, whether ML297 has an antinociceptive effect has not been elucidated.…”

Section: Introductionmentioning

confidence: 99%

Antinociceptive effect of selective G protein-gated inwardly rectifying K+ channel agonist ML297 in the rat spinal cord

et al. 2020

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The G protein-gated inwardly rectifying K + (GIRK) channels play important signaling roles in the central and peripheral nervous systems. However, the role of GIRK channel activation in pain signaling remains unknown mainly due to the lack of potent and selective GIRK channel activators until recently. The present study was designed to determine the effects and mechanisms of ML297, a selective GIRK1/2 activator, on nociception in the spinal cord by using behavioral studies and whole-cell patch-clamp recordings from substantia gelatinosa (SG) neurons. Rats were prepared for chronic lumber catheterization and intrathecal administration of ML297. The nociceptive flexion reflex was tested using an analgesy-meter, and the influence on motor performance was assessed using an accelerating rotarod. We also investigated pre- and post-synaptic actions of ML297 in spinal cord preparations by whole-cell patch-clamp recordings. Intrathecal administration of ML297 increased the mechanical nociceptive threshold without impairing motor function. In voltage-clamp mode of patch-clamp recordings, bath application of ML297 induced outward currents in a dose-dependent manner. The ML297-induced currents demonstrated specific equilibrium potential like other families of potassium channels. At high concentration, ML297 depressed miniature excitatory postsynaptic currents (mEPSCs) but not their amplitude. The ML297-induced outward currents and suppression of mEPSCs were not inhibited by naloxone, a μ-opioid receptor antagonist. These results demonstrated that intrathecal ML297 showed the antinociceptive effect, which was mediated through direct activation of pre- and post-synaptic GIRK channels. Selective GIRK channel activation is a promising strategy for the development of new agents against chronic pain and opioid tolerance.

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GIRK1-mediated inwardly rectifying potassium current suppresses the epileptiform burst activities and the potential antiepileptic effect of ML297

Cited by 24 publications

References 49 publications

De novo variants of NR4A2 are associated with neurodevelopmental disorder and epilepsy

De novo variants of NR4A2 are associated with neurodevelopmental disorder and epilepsy

Direct activation of G-protein-gated inward rectifying K+ channels promotes nonrapid eye movement sleep

Antinociceptive effect of selective G protein-gated inwardly rectifying K+ channel agonist ML297 in the rat spinal cord

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