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

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-κB, transcription factors activated by cAMP, calcium and IL-1β. Second messengers, cAMP and calcium, are triggered by TAAR1 activation, which is upregulated by IL-1β 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.

SUBMITTER: Cisneros IE

PROVIDER: S-EPMC7724046 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Methamphetamine (Meth) is a potent and commonly abused psychostimulant. Meth alters neuron and astrocyte activity; yet the underlying mechanism(s) is not fully understood. Here we assessed the impact of acute Meth on human fetal astrocytes (HFAs) using whole-cell patch-clamping. We found that HFAs displayed a large voltage-gated K+ efflux (IKv ) through Kv /Kv -like channels during membrane depolarization, and a smaller K+ influx (Ikir ) via inward-rectifying Kir /Kir -like channels during membrane hyperpolarization. Meth at a 'recreational' (20 ?M) or toxic/fatal (100 ?M) concentration depolarized resting membrane potential (RMP) and suppressed IKv/Kv-like . These changes were associated with a decreased time constant (?), and mimicked by blocking the two-pore domain K+ (K2P )/K2P -like and Kv /Kv -like channels, respectively. Meth also diminished IKir/Kir-like , but only at toxic/fatal levels. Given that Meth is a potent agonist for the trace amine-associated receptor type-1 (TAAR1), and TAAR1-coupled cAMP/cAMP-activated protein kinase (PKA) cascade, we further evaluated whether the Meth impact on K+ efflux was mediated by this pathway. We found that antagonizing TAAR1 with N-(3-Ethoxyphenyl)-4-(1-pyrrolidinyl)-3-(trifluoromethyl)benzamide (EPPTB) reversed Meth-induced suppression of IKv/Kv-like ; and inhibiting PKA activity by H89 abolished Meth effects on suppressing IKv/Kv-like . Antagonizing TAAR1 might also attenuate Meth-induced RMP depolarization. Voltage-gated Ca2+ currents were not detected in HFAs. These novel findings demonstrate that Meth suppresses IKv/Kv-like by facilitating the TAAR1/Gs /cAMP/PKA cascade and altering the kinetics of Kv /Kv -like channel gating, but reduces K2P /K2P -like channel activity through other pathway(s), in HFAs. Given that Meth-induced decrease in astrocytic K+ efflux through K2P /K2P -like and Kv /Kv -like channels reduces extracellular K+ levels, such reduction could consequently contribute to a decreased excitability of surrounding neurons. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.

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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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