Neuregulin 1 Controls Glutamate Uptake by Up-regulating Excitatory Amino Acid Carrier 1 (EAAC1)

Yu, Ha-Nul; Park, Woo-Kyu; Nam, Ki-Hoan; Song, Dae-Yong; Kim, Hye‐Sun; Baik, Tai-Kyoung; Woo, Ran-Sook

doi:10.1074/jbc.m114.591867

Cited by 22 publications

(25 citation statements)

References 47 publications

(66 reference statements)

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“…We also found evidence that mRNA levels of other genes important in synapse activity response, NRG1 and NR4A1, were affected by epilepsy-causing SIK1 sequence variations. NRG1 (neuregulin 1) regulates synaptic transmission, in part by controlling glutamate uptake, 36 and also maintaining GABAergic activity in parvalbumin(+) interneurons. 37 NR4A1 (Nur77) is an activity-dependent protein that regulates the density and distribution of dendritic spines and excitatory synapses.…”

Section: Discussionmentioning

confidence: 99%

Epilepsy-causing sequence variations in SIK1 disrupt synaptic activity response gene expression and affect neuronal morphology

et al. 2016

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SIK1 syndrome is a newly described developmental epilepsy disorder caused by heterozygous mutations in the salt-inducible kinase SIK1. To better understand the pathophysiology of SIK1 syndrome, we studied the effects of SIK1 pathogenic sequence variations in human neurons. Primary human fetal cortical neurons were transfected with a lentiviral vector to overexpress wild-type and mutant SIK1 protein. We evaluated the transcriptional activity of known downstream gene targets in neurons expressing mutant SIK1 compared with wild type. We then assayed neuronal morphology by measuring neurite length, number and branching. Truncating SIK1 sequence variations were associated with abnormal MEF2C transcriptional activity and decreased MEF2C protein levels. Epilepsy-causing SIK1 sequence variations were associated with significantly decreased expression of ARC (activity-regulated cytoskeletal-associated) and other synaptic activity response element genes. Assay of mRNA levels for other MEF2C target genes NR4A1 (Nur77) and NRG1, found significantly, decreased the expression of these genes as well. The missense p.(Pro287Thr) SIK1 sequence variation was associated with abnormal neuronal morphology, with significant decreases in mean neurite length, mean number of neurites and a significant increase in proximal branches compared with wild type. Epilepsy-causing SIK1 sequence variations resulted in abnormalities in the MEF2C-ARC pathway of neuronal development and synapse activity response. This work provides the first insights into the mechanisms of pathogenesis in SIK1 syndrome, and extends the ARX-MEF2C pathway in the pathogenesis of developmental epilepsy.

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Section: Discussionmentioning

confidence: 99%

Epilepsy-causing sequence variations in SIK1 disrupt synaptic activity response gene expression and affect neuronal morphology

et al. 2016

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“…Recently it was found that, neuregulin 1, an agonist for the ErbB4 tyrosine kinase receptor increases EAAT3 expression in C6 glioma cells and rat cortical cultures (Yu et al, 2015). A previous screen on mice deficient in another tyrosine kinase receptor, c-ros showed decreased EAAT3 expression, consistent with tyrosine kinase receptor-mediated increase in EAAT3 expression (Cooper et al, 2003).…”

Section: Regulation Of Eaat3mentioning

confidence: 99%

The importance of the excitatory amino acid transporter 3 (EAAT3)

Bjørn‐Yoshimoto

Underhill

2016

Neurochemistry International

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The neuronal excitatory amino acid transporter 3 (EAAT3) is fairly ubiquitously expressed in the brain, though it does not necessarily maintain the same function everywhere. It is important in maintaining low local concentrations of glutamate, where its predominant post-synaptic localization can buffer nearby glutamate receptors and modulate excitatory neurotransmission and synaptic plasticity. It is also the main neuronal cysteine uptake system acting as the rate-limiting factor for the synthesis of glutathione, a potent antioxidant, in EAAT3 expressing neurons, while on GABAergic neurons, it is important in supplying glutamate as a precursor for GABA synthesis. Several diseases implicate EAAT3, and modulation of this transporter could prove a useful therapeutic approach. Regulation of EAAT3 could be targeted at several points for functional modulation, including the level of transcription, trafficking and direct pharmacological modulation, and indeed, compounds and experimental treatments have been identified that regulate EAAT3 function at different stages, which together with observations of EAAT3 regulation in patients is giving us insight into the endogenous function of this transporter, as well as the consequences of altered function. This review summarizes work done on elucidating the role and regulation of EAAT3.

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“…Neuregulin-1 (NRG1) is well known to play an essential role in neuronal development, synapse formation, [7,8] and neuronal circuits. [9,10] NRG1 acts by activating the ErbB receptor tyrosine kinases. [11] Both NRG1 and its receptors are distributed throughout brain regions that are critical for higher cognitive functions in adult animals, [12,13] which suggests a role of NRG1 in adult or aged brains.…”

Section: Introductionmentioning

confidence: 99%

Blocking the phosphatidylinositol 3-kinase pathway inhibits neuregulin-1-mediated rescue of neurotoxicity induced by Aβ1–42

Baik

Kim

Kang

et al. 2016

Journal of Pharmacy and Pharmacology

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Neuregulin 1 Controls Glutamate Uptake by Up-regulating Excitatory Amino Acid Carrier 1 (EAAC1)

Cited by 22 publications

References 47 publications

Epilepsy-causing sequence variations in SIK1 disrupt synaptic activity response gene expression and affect neuronal morphology

Epilepsy-causing sequence variations in SIK1 disrupt synaptic activity response gene expression and affect neuronal morphology

The importance of the excitatory amino acid transporter 3 (EAAT3)

Blocking the phosphatidylinositol 3-kinase pathway inhibits neuregulin-1-mediated rescue of neurotoxicity induced by Aβ1–42

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