Nedd4-2 (NEDD4L) controls intracellular Na+-mediated activity of voltage-gated sodium channels in primary cortical neurons

Ekberg, Jenny; Boase, Natasha A.; Rychkov, Grigori Y.; Manning, James A.; Poronnik, Philip; Kumar, Sharad

doi:10.1042/bj20131275

Cited by 38 publications

(32 citation statements)

References 21 publications

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“…These data are in agreement with findings in cortical neurons where Nedd4-2 has been shown to mediate activation-induced down regulation of NaV that control neuronal excitability8. The significant increase in inflammatory pain points to Nedd4-2 as a major player contributing to the pathophysiology of pain.…”

Section: Discussionsupporting

confidence: 91%

“…For example, brain deletion of Nedd4-2 leads to increased ENaC expression and hypertension induced by a high-salt diet that can be prevented by central infusion of the ENaC blocker benzamil7. However, Nedd4-2 can also regulate glutamate, dopamine and the CHT-1 choline transporters, and interacts with a number of neuronal NaV channels in cortical and dorsal root ganglia (DRG) neurons89101112. Recently, the identification of a Nedd4L missense mutation in a patient with epileptic encephalopathy and the isolation of missense mutations in highly conserved residues of Nedd4-2 in families with photosensitive generalized epilepsy has suggested that this E3 ligase, in addition to hypertension, is an epilepsy associated gene and can contribute to CNS pathologies13.…”

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confidence: 99%

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Nedd4-2 haploinsufficiency causes hyperactivity and increased sensitivity to inflammatory stimuli

Yanpallewar

Wang

Koh

et al. 2016

Sci Rep

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Nedd4-2 (NEDD4L in humans) is a ubiquitin protein ligase best known for its role in regulating ion channel internalization and turnover. Nedd4-2 deletion in mice causes perinatal lethality associated with increased epithelial sodium channel (ENaC) expression in lung and kidney. Abundant data suggest that Nedd4-2 plays a role in neuronal functions and may be linked to epilepsy and dyslexia in humans. We used a mouse model of Nedd4-2 haploinsufficiency to investigate whether an alteration in Nedd4-2 levels of expression affects general nervous system functions. We found that Nedd4-2 heterozygous mice are hyperactive, have increased basal synaptic transmission and have enhanced sensitivity to inflammatory pain. Thus, Nedd4-2 heterozygous mice provide a new genetic model to study inflammatory pain. These data also suggest that in human, SNPs affecting NEDD4L levels may be involved in the development of neuropsychological deficits and peripheral neuropathies and may help unveil the genetic basis of comorbidities.

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Section: Discussionsupporting

confidence: 91%

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confidence: 99%

Nedd4-2 haploinsufficiency causes hyperactivity and increased sensitivity to inflammatory stimuli

Yanpallewar

Wang

Koh

et al. 2016

Sci Rep

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“…; Ekberg et al . ), Nedd4‐2 has never been shown to exert ubiquitin E3 ligase activity toward GluA1. To study whether Nedd4‐2 is capable of ubiquitinating GluA1, we co‐expressed GluA1 and Nedd4‐2 into HEK293 cells and observed strong ubiquitination on GluA1 (Fig.…”

Section: Resultsmentioning

confidence: 99%

The tumor suppressor p53 guides GluA1 homeostasis through Nedd4‐2 during chronic elevation of neuronal activity

Jewett

Zhu

Tsai

2015

Journal of Neurochemistry

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Chronic activity perturbation in neurons can trigger homeostatic mechanisms to restore the baseline function. Although the importance and dysregulation of neuronal activity homeostasis has been implicated in neurological disorders such as epilepsy, the complete signaling by which chronic changes in neuronal activity initiate the homeostatic mechanisms is unclear. We report here that the tumor suppressor p53 and its signaling are involved in neuronal activity homeostasis. Upon chronic elevation of neuronal activity in primary cortical neuron cultures, the ubiquitin E3 ligase, murine double minute-2 (Mdm2), is phosphorylated by the kinase Akt. Phosphorylated Mdm2 triggers the degradation of p53 and subsequent induction of a p53 target gene, neural precursor cell expressed developmentally down-regulated gene 4-like (Nedd4-2). Nedd4-2 encodes another ubiquitin E3 ligase. We identified glutamate receptor subunit 1 (GluA1), subunit of alphaamino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors as a novel substrate of Nedd4-2. The regulation of GluA1 level is known to be crucial for neuronal activity homeostasis. We confirmed that, by pharmacologically inhibiting Mdm2-mediated p53 degradation or genetically reducing Nedd4-2 in a mouse model, the GluA1 ubiquitination and down-regulation induced by chronically elevated neuronal activity are both attenuated. Our findings demonstrate the first direct function of p53 in neuronal homeostasis and elucidate a new mechanism by which cortical neurons respond to chronic activity perturbation. Keywords: GluA1, Mdm2, Nedd4-2, neuronal activity, p53, ubiquitination. The ubiquitin E3 ligase, murine double minute-2 (Mdm2), and its substrate p53, are well known in the regulation of apoptosis (Dornan et al. 2004), cell cycle control (Goldberg et al. 2002;Zhang and Zhang 2008), and cellular stress Received May 3, 2015; revised manuscript received July 9, 2015; accepted July 27, 2015.Address correspondence and reprint requests to Nien-Pei Tsai, PhD, 407 South Goodwin Ave., Urbana, IL 61801, USA. E-mail:nptsai@illi nois.eduAbbreviations used: AMPA, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; DMSO, dimethyl sulfoxide; GluA1, glutamate receptor subunit 1; GluA2, glutamate receptor subunit 2; HA, hemagglutinin; HEK, human embryonic kidney; Nedd4-1, neural precursor cell expressed developmentally down-regulated protein 4; Nedd4-2, neural precursor cell expressed developmentally down-regulated gene 4-like. 226

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“…In addition to GluA1, other neuronal substrates of Nedd4-2 potentially involved in neuronal activity regulation are voltage-gated sodium channels Na v 1.6 and voltage-gated potassium channels K v 7.3/KCNQ3 [9–12]. These two substrates are both crucial to modulating action potential firing and intrinsic excitability.…”

Section: Discussionmentioning

confidence: 99%

“…Because of an N-terminal lipid-binding domain, Nedd4-2 has high affinity toward binding and ubiquitinating membrane proteins [8]. Several neuronal membrane substrates of Nedd4-2 have been identified, such as voltage-gated sodium channel Na v 1.6 [9], voltage-gated potassium channels K v 7/KCNQ [10–12], neurotrophin receptor TrkA [13, 14] and the GluA1 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) [15]. Our previous work has demonstrated elevated seizure susceptibility in mice when Nedd4-2 is knocked down [16].…”

Section: Introductionmentioning

confidence: 99%

Epilepsy-associated gene Nedd4-2 mediates neuronal activity and seizure susceptibility through AMPA receptors

et al. 2017

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The neural precursor cell expressed developmentally down-regulated gene 4–2, Nedd4-2, is an epilepsy-associated gene with at least three missense mutations identified in epileptic patients. Nedd4-2 encodes a ubiquitin E3 ligase that has high affinity toward binding and ubiquitinating membrane proteins. It is currently unknown how Nedd4-2 mediates neuronal circuit activity and how its dysfunction leads to seizures or epilepsies. In this study, we provide evidence to show that Nedd4-2 mediates neuronal activity and seizure susceptibility through ubiquitination of GluA1 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, (AMPAR). Using a mouse model, termed Nedd4-2andi, in which one of the major forms of Nedd4-2 in the brain is selectively deficient, we found that the spontaneous neuronal activity in Nedd4-2andi cortical neuron cultures, measured by a multiunit extracellular electrophysiology system, was basally elevated, less responsive to AMPAR activation, and much more sensitive to AMPAR blockade when compared with wild-type cultures. When performing kainic acid-induced seizures in vivo, we showed that elevated seizure susceptibility in Nedd4-2andi mice was normalized when GluA1 is genetically reduced. Furthermore, when studying epilepsy-associated missense mutations of Nedd4-2, we found that all three mutations disrupt the ubiquitination of GluA1 and fail to reduce surface GluA1 and spontaneous neuronal activity when compared with wild-type Nedd4-2. Collectively, our data suggest that impaired GluA1 ubiquitination contributes to Nedd4-2-dependent neuronal hyperactivity and seizures. Our findings provide critical information to the future development of therapeutic strategies for patients who carry mutations of Nedd4-2.

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Nedd4-2 (NEDD4L) controls intracellular Na+-mediated activity of voltage-gated sodium channels in primary cortical neurons

Cited by 38 publications

References 21 publications

Nedd4-2 haploinsufficiency causes hyperactivity and increased sensitivity to inflammatory stimuli

Nedd4-2 haploinsufficiency causes hyperactivity and increased sensitivity to inflammatory stimuli

The tumor suppressor p53 guides GluA1 homeostasis through Nedd4‐2 during chronic elevation of neuronal activity

Epilepsy-associated gene Nedd4-2 mediates neuronal activity and seizure susceptibility through AMPA receptors

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