Genetic Knockout of TRPM2 Increases Neuronal Excitability of Hippocampal Neurons by Inhibiting Kv7 Channel in Epilepsy

Ying, Yingchao; Gong, Lifen; Tao, Xiaohan; Ding, Junchao; Chen, Nannan; Yao, Yinping; Liu, Jiajing; Chen, Chen; Zhu, Tao; Jiang, Peifang

doi:10.1007/s12035-022-02993-2

Cited by 5 publications

(2 citation statements)

References 80 publications

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“…As well as in the CNS, Kv7.2 and Kv7.3 are widely present in the PNS, where they play an important role in the nociceptive pathway. Indeed, an alteration of their currents may cause a strong neuronal hyperexcitability, leading to different physiopathologies such as epilepsy, peripheral sensitization and neuropathic pain [ 52 , 73 , 75 , 76 ].…”

Section: Biophysical Properties Of Transporters/ion Channels Of Interestmentioning

confidence: 99%

Ion Channel and Transporter Involvement in Chemotherapy-Induced Peripheral Neurotoxicity

Pozzi,

Terribile,

Cherchi

et al. 2024

IJMS

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The peripheral nervous system can encounter alterations due to exposure to some of the most commonly used anticancer drugs (platinum drugs, taxanes, vinca alkaloids, proteasome inhibitors, thalidomide), the so-called chemotherapy-induced peripheral neurotoxicity (CIPN). CIPN can be long-lasting or even permanent, and it is detrimental for the quality of life of cancer survivors, being associated with persistent disturbances such as sensory loss and neuropathic pain at limb extremities due to a mostly sensory axonal polyneuropathy/neuronopathy. In the state of the art, there is no efficacious preventive/curative treatment for this condition. Among the reasons for this unmet clinical and scientific need, there is an uncomplete knowledge of the pathogenetic mechanisms. Ion channels and transporters are pivotal elements in both the central and peripheral nervous system, and there is a growing body of literature suggesting that they might play a role in CIPN development. In this review, we first describe the biophysical properties of these targets and then report existing data for the involvement of ion channels and transporters in CIPN, thus paving the way for new approaches/druggable targets to cure and/or prevent CIPN.

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Section: Biophysical Properties Of Transporters/ion Channels Of Interestmentioning

confidence: 99%

Ion Channel and Transporter Involvement in Chemotherapy-Induced Peripheral Neurotoxicity

Pozzi,

Terribile,

Cherchi

et al. 2024

IJMS

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“…The expression of the TRPM2 channel in diverse cell types has been well-documented [30,39]. We began our study by verifying the TRPM2 channel's expression in HT22 cells using immunofluorescent microscopy.…”

Section: Expression Of Trpm2 and Cu-induced Increase In The [Ca 2+ ]Imentioning

confidence: 99%

Signalling Mechanism in TRPM2-dependent Copper- induced HT22 Cell Death

Rathakrishnan,

Hazanol,

Dali

et al. 2023

J Biochem Microbiol Biotechnol

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Copper (Cu) is one of the critical elements needed by the human body. However, this metal can cause cytotoxicity when present in excess amounts. In this study, we used HT22 hippocampus cells to examine the function of the Ca2+-permeable transient receptor melastatin 2 (TRPM2) channel in Cu-induced neuronal cell death and the underlying mechanisms. Immunocytochemistry, single-cell imaging, acridine orange/propidium iodide (AO/PI) cell death assay and immunofluorescence microscopy were applied to interpret the mechanisms involved in Cu-induced HT22 cell death. Treatment of 30-300 μM Cu induced an increase in the [Ca2+]i in HT22 cells. Further analysis indicates that Cu exposure induced substantial HT22 cell death. Such response on HT22 cells was significantly inhibited by 2-aminoethoxydiphenyl borate (2-APB) and N-(p-amylcinnamoyl)anthranilic acid (ACA), TRPM2 channel inhibitors. Furthermore, Cu-induced HT22 cell death was suppressed by pharmacologically inhibiting poly(ADPR) polymerase (PARP) using PJ-34 and DPQ. It is known that the activation of TRPM2 channel is via the increase of intracellular reactive oxygen species (ROS). A significant concentration-dependent increase in the generation of ROS was observed in HT22 following the treatment with 30-300 μM Cu. Additionally, Cu-induced HT22 cell death was ablated by inhibiting PKC using CTC, a PKC inhibitor and NADPH oxidase (NOX) using DPI, a NOX generic inhibitor and GKT137831, a NOX1/4-specific inhibitor. Overall, our present study provides evidence suggesting that PKC/NOX/ROS/PARP is an important signalling pathway in Cu-induced activation of the TRPM2 channel and increase in the [Ca2+]i which eventually results in the toxicity of HT22 cells. These results provide new insights into the mechanisms of neurological-associated Cu-induced diseases.

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Pharmacologically targeting transient receptor potential channels for seizures and epilepsy: Emerging preclinical evidence of druggability

Jiang

2023

Pharmacology & Therapeutics

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Genetic Knockout of TRPM2 Increases Neuronal Excitability of Hippocampal Neurons by Inhibiting Kv7 Channel in Epilepsy

Cited by 5 publications

References 80 publications

Ion Channel and Transporter Involvement in Chemotherapy-Induced Peripheral Neurotoxicity

Ion Channel and Transporter Involvement in Chemotherapy-Induced Peripheral Neurotoxicity

Signalling Mechanism in TRPM2-dependent Copper- induced HT22 Cell Death

Pharmacologically targeting transient receptor potential channels for seizures and epilepsy: Emerging preclinical evidence of druggability

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