4.7 Article

Nedd4-2 haploinsufficiency in mice causes increased seizure susceptibility and impaired Kir4.1 ubiquitination

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ELSEVIER
DOI: 10.1016/j.bbadis.2021.166128

Keywords

Nedd4-2; Kir4.1; Ubiquitination; Epilepsy; Proteomics

Funding

  1. National Key Technologies R&D Program of China [2016YFC1000702]
  2. Outstanding Scientific Fund of Shengjing Hospital [ME57]

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The study showed that Nedd4-2 haploinsufficiency can increase susceptibility to seizures in mice, and impaired ubiquitination of the Kir4.1 channel may be related to this.
Neural precursor cell expressed developmentally down-regulated gene 4-like (NEDD4-2) encodes a ubiquitin E3 ligase that is involved in epileptogenesis with mechanisms needing further investigation. We constructed a novel Nedd4-2(+/-) mouse model with half level of both Nedd4-2 long and short isoforms in the brain. Nedd4-2 haploinsufficiency caused increased susceptibility and severity of pentylenetetrazole (PTZ)-induced seizures. Of the 3379 proteins identified by the hippocampal proteomic analysis, 55 were considered altered in Nedd4-2(+/-) mice compared with wild-type control, among which the inwardly rectifying K+ channel Kir4.1 was up-regulated by 1.83-fold. Kir4.1 was subsequently confirmed to be less ubiquitinated in response to comprised Nedd4-2 in mouse brains and C6 cells. Kir4.1 associated with Nedd4-2 through the threonine(312)-proline motif in the intracellular domain by target mutagenesis. Adaptor protein 14-3-3 facilitated Nedd4-2-mediated ubiquitination of Kir4.1. Our data consolidate the detailed molecular mechanism of Nedd4-2-mediated Kir4.1 ubiquitination, and provide a possible relationship between increased seizure susceptibility and impaired Kir4.1 ubiquitination in the brain.

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