Abstract
Excitatory amino acid carrier 1 (EAAC1) is an important subtype of excitatory amino acid transporters (EAATs) and is the route for neuronal cysteine uptake. CoCl2 is not only a hypoxia-mimetic reagent but also an oxidative stress inducer. Here, we found that CoCl2 induced significant EAAC1 overexpression in SH-SY5Y cells and the hippocampus of mice. Transient transfection of EAAC1 reduced CoCl2-induced cytotoxicity in SH-SY5Y cells. Based on this result, upregulation of EAAC1 expression by CoCl2 is thought to represent a compensatory response against oxidative stress in an acute hypoxic state. We further demonstrated that pretreatment with Neuregulin-1 (NRG1) rescued CoCl2-induced upregulation of EAAC1 and tau expression. NRG1 plays a protective role in the CoCl2-induced accumulation of reactive oxygen species (ROS) and reduction in antioxidative enzyme (SOD and GPx) activity. Moreover, NRG1 attenuated CoCl2-induced apoptosis and cell death. NRG1 inhibited the CoCl2-induced release of cleaved caspase-3 and reduction in Bcl-XL levels. Our novel finding suggests that NRG1 may play a protective role in hypoxia through the inhibition of oxidative stress and thereby maintain normal EAAC1 expression levels.
Highlights
Excitatory amino acid carrier 1 (EAAC1, referred to as EAAT3) is one neuronal subtype of excitatory amino acid transporter (EAAT) that is ubiquitously expressed in the central nervous system (CNS)
We found that there was a dose-dependent increase in EAAC1 expression after 24 h of Cobalt chloride (CoCl2) (50–500 μM) treatment (Fig. 1a)
Treatment with 100 μM CoCl2 significantly reduced the activity of Glutathione peroxidase (GPx)
Summary
Excitatory amino acid carrier 1 (EAAC1, referred to as EAAT3) is one neuronal subtype of excitatory amino acid transporter (EAAT) that is ubiquitously expressed in the central nervous system (CNS). The intracellular response to hypoxia is regulated by hypoxia inducible factor-1 (HIF-1). Kim et al Mol Brain (2020) 13:153 transcription factor, and a heterodimer consisting of an oxygen-dependent regulatory HIF-1α subunit and a constitutively expressed HIF-lβ subunit that acts as a master regulator of adaptation to a low oxygen environment in the cell [9]. Hypoxia leads to a rapid increase in spontaneous vesicular glutamate release [10] and impaired glutamate uptake [11,12,13]. EAAC1 was increased at the transcript level in C6 cells by hypoxia [14]. Oxygen–glucose deprivation (OGD) induced the protein expression of EAAC1 in pure and mixed neuronal cultures and promoted EAAT3 activity, which increased glutamate uptake into cultured neurons [15]. EAAC1 transcript levels were transiently upregulated during the reperfusion phase in ischemia–reperfusion models [15]. Ischemia–reperfusion leads to oxidative stress and an accompanying transient increase in EAAT3 immunoreactivity in the hippocampus [16]
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