Wang, Y; Yang, H; Li, N; Wang, L; Guo, C; Ma, W; Liu, S; ... Huang, Z; + view all Wang, Y; Yang, H; Li, N; Wang, L; Guo, C; Ma, W; Liu, S; Peng, C; Chen, J; Song, H; Chen, H; Ma, X; Yi, J; Lian, J; Kong, W; Dong, J; Tu, X; Shah, M; Tian, X; Huang, Z; - view fewer (2024) A Novel Ubiquitin Ligase Adaptor PTPRN Suppresses Seizure Susceptibility through Endocytosis of NaV1.2 Sodium Channels. Advanced Science , Article 2400560. 10.1002/advs.202400560. (In press).

PDF Advanced Science - 2024 - Wang - A Novel Ubiquitin Ligase Adaptor PTPRN Suppresses Seizure Susceptibility through.pdf - Published Version Download (9MB)

Abstract

Intrinsic plasticity, a fundamental process enabling neurons to modify their intrinsic properties, plays a crucial role in shaping neuronal input-output function and is implicated in various neurological and psychiatric disorders. Despite its importance, the underlying molecular mechanisms of intrinsic plasticity remain poorly understood. In this study, a new ubiquitin ligase adaptor, protein tyrosine phosphatase receptor type N (PTPRN), is identified as a regulator of intrinsic neuronal excitability in the context of temporal lobe epilepsy. PTPRN recruits the NEDD4 Like E3 Ubiquitin Protein Ligase (NEDD4L) to NaV1.2 sodium channels, facilitating NEDD4L-mediated ubiquitination, and endocytosis of NaV1.2. Knockout of PTPRN in hippocampal granule cells leads to augmented NaV1.2-mediated sodium currents and higher intrinsic excitability, resulting in increased seizure susceptibility in transgenic mice. Conversely, adeno-associated virus-mediated delivery of PTPRN in the dentate gyrus region decreases intrinsic excitability and reduces seizure susceptibility. Moreover, the present findings indicate that PTPRN exerts a selective modulation effect on voltage-gated sodium channels. Collectively, PTPRN plays a significant role in regulating intrinsic excitability and seizure susceptibility, suggesting a potential strategy for precise modulation of NaV1.2 channels' function.

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