ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2010
Human immunodeficiency virus-1 Tat activates calpain proteases via the ryanodine receptor to enhance surface dopamine transporter levels and increase transporter-specific uptake and Vmax.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 57 citations in OpenAlex.
- Article
- Allosteric Modulation of Cannabinoid Type 1 Receptor by ZCZ011: Integration of In Vitro Pharmacology and Molecular Dynamics Simulation.ACS bio & med chem Au · 2025Article
- Xenon gas as a potential treatment for opioid use disorder, alcohol use disorder, and related disorders.Medical gas research · 2025Review
- HIV-1 Tat Impairment of Mitochondrial Respiration via Complexes I and II Can Be Ameliorated by Allopregnanolone in Opioid-Exposed or Opioid-Naïve Cells and Mice.Antioxidants (Basel, Switzerland) · 2025Article
- HIV-Tat Exacerbates the Actions of Atazanavir, Efavirenz, and Ritonavir on Cardiac Ryanodine Receptor (RyR2).International journal of molecular sciences · 2022Article
- GPR18 drives FAAH inhibition-induced neuroprotection against HIV-1 Tat-induced neurodegeneration.Experimental neurology · 2021Article
- Monoacylglycerol Lipase Inhibitor MJN110 Reduces Neuronal Hyperexcitability, Restores Dendritic Arborization Complexity, and Regulates Reward-Related Behavior in Presence of HIV-1 Tat.Frontiers in neurology · 2021Article
- Pregnane steroidogenesis is altered by HIV-1 Tat and morphine: Physiological allopregnanolone is protective against neurotoxic and psychomotor effects.Neurobiology of stress · 2020Article
- Article
- The long and the short of it: the MDM4 tail so far.Journal of molecular cell biology · 2019Review
- Neuroprotective effects of fatty acid amide hydrolase catabolic enzyme inhibition in a HIV-1 Tat model of neuroAIDS.Neuropharmacology · 2018Article
- Doxycycline-inducible and astrocyte-specific HIV-1 Tat transgenic mice (iTat) as an HIV/neuroAIDS model.Journal of neurovirology · 2018Review
- The role of human dopamine transporter in NeuroAIDS.Pharmacology & therapeutics · 2018Review
- HIV, Tat and dopamine transmission.Neurobiology of disease · 2017Review
- Endocannabinoids exert CBMolecular and cellular neurosciences · 2017Article
- Time-Dependent, HIV-Tat-Induced Perturbation of Human NeuronsFrontiers in molecular neuroscience · 2017Article
- Interference with CaFrontiers in physiology · 2017Article
- Dual roles of calpain in facilitating Coxsackievirus B3 replication and prompting inflammation in acute myocarditis.International journal of cardiology · 2016Article
- 5α-reduced progestogens ameliorate mood-related behavioral pathology, neurotoxicity, and microgliosis associated with exposure to HIV-1 Tat.Brain, behavior, and immunity · 2016Article
- HIV-1 transgenic rats display an increase in [(3)H]dopamine uptake in the prefrontal cortex and striatum.Journal of neurovirology · 2016Article
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
Abstract
Human immunodeficiency virus-associated neurological disease (HAND) still causes significant morbidity, despite success reducing viral loads with combination antiretroviral therapy. The dopamine (DA) system is particularly vulnerable in HAND. We hypothesize that early, "reversible" DAergic synaptic dysfunction occurs long before DAergic neuron loss. As such, aging human immunodeficiency virus (HIV)-infected individuals may be vulnerable to other age-related neurodegenerative diseases like Parkinson's disease (PD), underscoring the need to understand shared molecular targets in HAND and PD. Previously, we reported that the neurotoxic HIV-1 transactivating factor (Tat) acutely disrupts mitochondrial and endoplasmic reticulum calcium homeostasis via ryanodine receptor (RyR) activation. Here, we further report that Tat disrupts DA transporter (DAT) activity and function, resulting in increased plasma membrane (PM) DAT and increased DAT V(max), without changes in K(m) or total DAT protein. Tat also increases calpain protease activity at the PM, demonstrated by total internal reflection fluorescence microscopy of a cleavable fluorescent calpain substrate. Tat-increased PM DAT and calpain activity are blocked by the RyR antagonists ryanodine and dantrolene, the calpain inhibitor calpastatin, and by a specific inhibitor of GSK-3β. We conclude that Tat activates RyRs via a calcium- and calpain-mediated mechanism that upregulates DAT trafficking to the PM, and is independent of DAT protein synthesis, reinforcing the feasibility of RyR and GSK-3β inhibition as clinical therapeutic approaches for HAND. Finally, we provide key translational relevance for these findings by highlighting published human data of increased DAT levels in striata of HAND patients and by demonstrating similar findings in Tat-expressing transgenic mice.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.