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Journal of Neuroimmune Pharmacology

, Volume 7, Issue 3, pp 629–639 | Cite as

HIV-1 Tat Protein Decreases Dopamine Transporter Cell Surface Expression and Vesicular Monoamine Transporter-2 Function in Rat Striatal Synaptosomes

  • Narasimha M. Midde
  • Adrian M. Gomez
  • Jun ZhuEmail author
ORIGINAL ARTICLE

Abstract

The dopamine (DA) transporter (DAT) and vesicular monoamine transporter (VMAT2) proteins interact as a biochemical complex to regulate dopaminergic neurotransmission. We have reported that HIV-1Tat1–86 decreases the specific [3H]DA uptake and [3H]WIN 35,428 binding sites without a change in total DAT immunoreactivity in rat striatum (Zhu et al., 2009b). The present study determined the effects of Tat on DAT phosphorylation and trafficking, and vesicular [3H]DA uptake. Pre-incubation of rat striatal synaptosomes with the protein kinase C (PKC) inhibitor bisindolylmaleimide I (1 μM) completely blocked Tat1–86-induced reduction of [3H]DA uptake, indicating that Tat regulates DAT function through a PKC-dependent mechanism. After exposure of synaptosomes to Tat1–86 (1 μM), DAT immunoreactivity was decreased in plasma membrane enriched fractions (P3) and increased in vesicle-enriched fractions (P4) relative to controls without change in total synaptosomal fractions (P2), suggesting that Tat-induced inhibition of DA uptake is attributable to DAT internalization. Although both DAT and VMAT2 proteins are essential for the regulation of DA disposition in synapse and cytosol, Tat inhibited the specific [3H]DA uptake into vesicles (P4) and synaptosomes (P2) by 35 % and 26 %, respectively, inferring that the inhibitory effect of Tat was more profound in VMAT2 protein than in DAT protein. Taken together, the current study reveals that Tat inhibits DAT function through a PKC and trafficking-dependent mechanism and that Tat impacts the dopaminergic tone by regulating both DAT and VMAT2 proteins. These findings provide new insight into understanding the pharmacological mechanisms of HIV-1 viral protein-induced dysfunction of DA neurotransmission in HIV-infected patients.

Keywords

Dopamine transporter Vesicular monoamine transporter HIV-1 Tat Protein kinase C Uptake Trafficking 

Notes

Acknowledgements

This research was supported by grants from the National Institute on Drug Abuse to Jun Zhu (DA024275 and DA026721).

Conflicts of Interest

The authors declare no conflicts of interest.

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© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Narasimha M. Midde
    • 1
  • Adrian M. Gomez
    • 1
  • Jun Zhu
    • 1
    Email author
  1. 1.Department of Pharmaceutical and Biomedical Sciences, South Carolina College of PharmacyUniversity of South CarolinaColumbiaUSA

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