Prolonged inhibition of CaMKII results in hyperexcitability by increasing NaV1.2 expression and its interaction with CaM

Published: 9 November 2022| Version 1 | DOI: 10.17632/z4p8tj4jxv.1
Contributors:
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, Tomasz Boczek,
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Description

Dysfunction of calcium/calmodulin (CaM)-dependent kinase II (CaMKII) has been involved in hyperexcitability-related disorders including epilepsy. However, the exact mechanism by which CaMKII inhibits neuronal excitability remains to be elucidated. In the present study, we found that seizure-like events recorded by EEG in both wild-type and genetic epilepsy model rats were markedly augmented in response to the prolonged inhibition of CaMKII, indicating that the inactivation of CaMKII enhanced the neuronal excitability. Electrophysiological recording showed that CaMKII inhibition induced hyperexcitability of cultured hippocampal neurons and potentiation of neuronal activity in induced pluripotent stem cell (iPSC)-derived cortical neurons. We further revealed that CaMKII inhibition enhanced the persistent slow inactivating sodium current (INaP) of hippocampal neurons, which was attributed to increased neuronal expression of the voltage-gated sodium channel NaV1.2. Our findings suggest that NaV1.2 expression was transcriptionally upregulated by the negative regulator nuclear receptor subfamily 4 group A member 2 (NR4A2). Furthermore, CaMKII inhibition induced interaction between NaV1.2 and CaM through immunoprecipitation assay. Intriguingly, a peptide that antagonized the binding of CaM to the IQ domain of NaV1.2 prevented neuronal hyperexcitability induced by CaMKII inhibition in vivo and in vitro. Altogether, we unveil that prolonged CaMKII inhibition leads to hyperexcitability through increasing the expression of NaV1.2 and its association with CaM. Thus, our study uncovers a novel signaling mechanism by which CaMKII maintains to appropriate neuronal excitability.

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Institutions

China Medical University College of Pharmacy, China Medical University, Shandong University, Xuzhou Medical University, Boston Children's Hospital, China Medical University First Hospital

Categories

Neuronal Excitability, Epilepsy, Calmodulin

Funding

National Natural Science Foundation of China

81971212

National Natural Science Foundation of China

81471353

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