Chronic exposure to morphine decreases the expression of EAAT3 via opioid receptors in hippocampal neurons

Guo, Mingyan; Cao, Ding; Zhu, Siyu; Fu, Ganglan; Wu, Qiang; Liang, Jianjun; Cao, Minghui

doi:10.1016/j.brainres.2015.03.037

Cited by 12 publications

(9 citation statements)

References 25 publications

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“…Notably, chronic morphine treatment decreases EAAT3 expression through stimulation of opioid receptors in both rats, mice and cell lines (Mao et al, 2002). This was dependent on ubiquitination by NEDD4, an E3 ubiquitin ligase, which in turn was dependent on the phosphatase PTEN (Lim et al, 2005, Yang et al, 2008), though also EAAT3 mRNA decreases (Guo et al, 2015). The expression of EAAT3 was time-dependent, and after 12 hours of withdrawal, the levels returned to baseline (Guo et al, 2015).…”

Section: Regulation Of Eaat3mentioning

confidence: 99%

“…This was dependent on ubiquitination by NEDD4, an E3 ubiquitin ligase, which in turn was dependent on the phosphatase PTEN (Lim et al, 2005, Yang et al, 2008), though also EAAT3 mRNA decreases (Guo et al, 2015). The expression of EAAT3 was time-dependent, and after 12 hours of withdrawal, the levels returned to baseline (Guo et al, 2015). Morphine tolerance was abolished by blocking NR2B containing NMDARs in rats (Mao et al, 2002) and NR2B, but not NR2A, NR2C or NR2D NMDAR subunit expression was increased by chronic morphine treatment in dorsal root ganglion neurons (Gong et al, 2015).…”

Section: Regulation Of Eaat3mentioning

confidence: 99%

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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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Section: Regulation Of Eaat3mentioning

confidence: 99%

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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“…Interestingly, the present finding also suggests a possibility that oxidative stress can regulate EAAC1 since NAC prevented the E-induced EAAC1 loss ( Figure 7 C). In support of this finding, under stressful conditions, such as oxidative and chemical stress, regulation and/or alteration of EAAC1 are evident at the level of expression, activity, and its membrane trafficking [ 49 , 50 , 51 , 52 ]. Clinically, NAC is the widely used Cys prodrug due to its safety, tolerability, and its ability to undergo rapid hydrolysis to deliver Cys immediately following cellular entry [ 46 , 53 , 54 ].…”

Section: Discussionmentioning

confidence: 78%

Ethanol (E) Impairs Fetal Brain GSH Homeostasis by Inhibiting Excitatory Amino-Acid Carrier 1 (EAAC1)-Mediated Cysteine Transport

Patel

Mahimainathan

Narasimhan

et al. 2017

IJMS

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Central among the fetotoxic responses to in utero ethanol (E) exposure is redox-shift related glutathione (GSH) loss and apoptosis. Previously, we reported that despite an E-generated Nrf2 upregulation, fetal neurons still succumb. In this study, we investigate if the compromised GSH results from an impaired inward transport of cysteine (Cys), a precursor of GSH in association with dysregulated excitatory amino acid carrier1 (EAAC1), a cysteine transporter. In utero binge model involves administration of isocaloric dextrose or 20% E (3.5 g/kg)/ by gavage at 12 h intervals to pregnant Sprague Dawley (SD) rats, starting gestation day (gd) 17 with a final dose on gd19, 2 h prior to sacrifice. Primary cerebral cortical neurons (PCNs) from embryonic day 16–17 fetal SD rats were the in vitro model. E reduced both PCN and cerebral cortical GSH and Cys up to 50% and the abridged GSH could be blocked by administration of N-acetylcysteine. E reduced EAAC1 protein expression in utero and in PCNs (p < 0.05). This was accompanied by a 60–70% decrease in neuron surface expression of EAAC1 along with significant reductions of EAAC1/Slc1a1 mRNA (p < 0.05). In PCNs, EAAC1 knockdown significantly decreased GSH but not oxidized glutathione (GSSG) illustrating that while not the sole provider of Cys, EAAC1 plays an important role in neuron GSH homeostasis. These studies strongly support the concept that in both E exposed intact fetal brain and cultured PCNs a mechanism underlying E impairment of GSH homeostasis is reduction of import of external Cys which is mediated by perturbations of EAAC1 expression/function.

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“…It cannot be excluded that also naltrindole itself may, to a certain extent, possess such properties. The fact that naltrindole reversed morphine effect in cells expressing both MORs and DORs may be also interpreted as an indirect hint that naltrindole may interact not only with DORs but also with MORs (Guo et al 2015). We can speculate that bell-shaped concentration dependence of naltrindole effect on sodium current may be due to mixed interaction of this drug with MORs and ORL1s.…”

Section: Discussionmentioning

confidence: 87%

SNC80 and naltrindole modulate voltage-dependent sodium, potassium and calcium channels via a putatively delta opioid receptor-independent mechanism

Moravcikova

Královičová²,

Lacinová³

2018

gpb

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SNC80 was designed as a highly selective nonpeptide delta opioid receptor (DOR) agonist. Antidepressant-like and antinociceptive effects of this compound were demonstrated in animal models. Naltrindole was synthetized as a highly selective DOR antagonist. Its antitussive and antinociceptive effects were reported. Observed effects of SNC80 and naltrindole may be accompanied by changes in neuronal excitability including modulation of voltage-dependent ion channels. We investigated possible DOR-independent modulation of neuronal sodium, calcium and potassium currents by both agents. NG108-15 cells lacking expression of DOR protein were used as model of neuronal cells. Cells were differentiated into neuronal phenotype by exposure to dibutyryl cyclic-AMP (dbcAMP). Lack of DORs expression in NG108-15 cells and the presence of DOR expression in brain and neuronal cultures were demonstrated by Western blot analysis. Both SNC80 and naltrindole exerted low to moderate modulatory effects on voltage-dependent ion currents. SNC80 weakly inhibited sodium current, potentiated calcium current, and did not act on potassium channels. Naltrindole inhibited sodium current, did not act on calcium current and inhibited potassium current at a high concentration. Such effects should be taken into account when these compounds are used for investigation of DOR-mediated signaling pathways.

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Chronic exposure to morphine decreases the expression of EAAT3 via opioid receptors in hippocampal neurons

Cited by 12 publications

References 25 publications

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

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

Ethanol (E) Impairs Fetal Brain GSH Homeostasis by Inhibiting Excitatory Amino-Acid Carrier 1 (EAAC1)-Mediated Cysteine Transport

SNC80 and naltrindole modulate voltage-dependent sodium, potassium and calcium channels via a putatively delta opioid receptor-independent mechanism

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