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| Content Provider | frontiers |
|---|---|
| Author | Cisneros, Irma E. Ghorpade, Anuja Borgmann, Kathleen |
| Abstract | Methamphetamine (METH) use, referred to as methamphetamine use disorder (MUD), results in neurocognitive decline, a characteristic shared with HIV-associated neurocognitive disorders (HAND). MUD exacerbates HAND partly through glutamate dysregulation. Astrocyte excitatory amino acid transporter (EAAT)-2 is responsible for >90% of glutamate uptake from the synaptic environment and is significantly decreased with METH and HIV-1. Our previous work demonstrated astrocyte trace amine associated receptor (TAAR) 1 to be involved in EAAT-2 regulation. Astrocyte EAAT-2 is regulated at the transcriptional level by cAMP responsive element binding (CREB) protein and NF-B, transcription factors activated by cAMP, calcium and IL-1. Second messengers, cAMP and calcium, are triggered by TAAR1 activation, which is upregulated by IL-1METH-mediated increases in these second messengers and signal transduction pathways have not been shown to directly decrease astrocyte EAAT-2. We propose CREB activation serves as a master regulator of EAAT-2 transcription, downstream of METH-induced TAAR1 activation. To investigate the temporal order of events culminating in CREB activation, genetically encoded calcium indicators, GCaMP6s, were used to visualize METH-induced calcium signaling in primary human astrocytes. RNA interference and pharmacological inhibitors targeting or blocking cAMP-dependent protein kinase A and calcium/calmodulin kinase II confirmed METH-induced regulation of EAAT-2 and resultant glutamate clearance. Furthermore, we investigated METH-mediated CREB phosphorylation at both serine 133 and 142, the co-activator and co-repressor forms, respectively. Overall, this work revealed METH-induced differential CREB phosphorylation is a critical regulator for EAAT-2 function and may thus serve as a mechanistic target for the attenuation of METH-induced excitotoxicity in the context of HAND. |
| ISSN | 16642295 |
| DOI | 10.3389/fneur.2020.593146 |
| Volume Number | 11 |
| Journal | Frontiers in Neurology |
| Language | English |
| Publisher Date | 2020-11-25 |
| Access Restriction | Open |
| Subject Keyword | Cyclic AMP Inflammation Calcium Excitotoxicity Glutamate Kinase activation |
| Content Type | Text |
| Resource Type | Article |
| Subject | Neurology Neurology (clinical) |
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