Methamphetamine Activates Trace Amine Associated Receptor 1 to Regulate Astrocyte Excitatory Amino Acid Transporter-2 via Differential CREB Phosphorylation During HIV-Associated Neurocognitive Disorders

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dc.creatorCisneros, Irma E.
dc.creatorGhorpade, Anuja
dc.creatorBorgmann, Kathleen
dc.creator.orcid0000-0003-0897-390X (Borgmann, Kathleen)
dc.creator.orcid0000-0002-8965-0979 (Cisneros, Irma)
dc.date.accessioned2022-07-12T16:34:46Z
dc.date.available2022-07-12T16:34:46Z
dc.date.issued2020-11-25
dc.description.abstractMethamphetamine (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-kappaB, transcription factors activated by cAMP, calcium and IL-1beta. Second messengers, cAMP and calcium, are triggered by TAAR1 activation, which is upregulated by IL-1beta METH-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.
dc.description.sponsorshipThis work was supported by R01DA039789 from NIDA to AG and then Dr. Michael Mathis, and F31DA037832 from NIDA to IC. We appreciate the assistance of the Laboratory of Developmental Biology for providing us with human brain tissues, which is supported by NIH Award Number 5R24HD0008836 from the Eunice Kennedy Shriver National Institute of Child Health & Human Development.
dc.identifier.citationCisneros, I. E., Ghorpade, A., & Borgmann, K. (2020). Methamphetamine Activates Trace Amine Associated Receptor 1 to Regulate Astrocyte Excitatory Amino Acid Transporter-2 via Differential CREB Phosphorylation During HIV-Associated Neurocognitive Disorders. Frontiers in neurology, 11, 593146. https://doi.org/10.3389/fneur.2020.593146
dc.identifier.issn1664-2295
dc.identifier.urihttps://hdl.handle.net/20.500.12503/31581
dc.identifier.volume11
dc.publisherFrontiers Media S.A.
dc.relation.urihttps://doi.org/10.3389/fneur.2020.593146
dc.rights.holderCopyright © 2020 Cisneros, Ghorpade and Borgmann.
dc.rights.licenseAttribution 4.0 International (CC BY 4.0)
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourceFrontiers in Neurology
dc.subjectcalcium
dc.subjectcyclic AMP
dc.subjectexcitotoxicity
dc.subjectglutamate
dc.subjectinflammation
dc.subjectkinase activation
dc.titleMethamphetamine Activates Trace Amine Associated Receptor 1 to Regulate Astrocyte Excitatory Amino Acid Transporter-2 via Differential CREB Phosphorylation During HIV-Associated Neurocognitive Disorders
dc.typeArticle
dc.type.materialtext

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