The HIV-1 Viral Protein Tat Increases Glutamate and Decreases GABA Exocytosis from Human and Mouse Neocortical Nerve Endings

Abstract

Human immunodeficiency virus-1 (HIV-1)-encoded transactivator of transcription (Tat) potentiated the depolarization-evoked exocytosis of [(3)H]D-aspartate ([(3)H]D-ASP) from human neocortical terminals. The metabotropic glutamate (mGlu) 1 receptor antagonist 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt) prevented this effect, whereas the mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl) pyridine hydrochloride (MPEP) was ineffective. Western blot analysis showed that human neocortex synaptosomes possess mGlu1 and mGlu5 receptors. Tat potentiated the K(+)-evoked release of [(3)H]D-ASP or of endogenous glutamate from mouse neocortical synaptosomes in a CPCCOEt-sensitive and MPEP-insensitive manner. Deletion of mGlu1 receptors (crv4/crv4 mice) or mGlu5 receptors (mGlu5(-/-)mouse) silenced Tat effects. Tat enhanced inositol 1,4,5-trisphosphate production in human and mouse neocortical synaptosomes, consistent with the involvement of group I mGlu receptors. Tat inhibited the K(+)-evoked release of [(3)H]gamma-aminobutyric acid ([(3)H]GABA) from human synaptosomes and that of endogenous GABA or [(3)H]GABA from mouse nerve terminals; the inhibition was insensitive to CPCCOEt or MPEP. Tat-induced effects were retained by Tat(37-72) but not by Tat(48-85). In mouse neocortical slices, Tat facilitated the K(+)- and the veratridine-induced release of [(3)H]D-ASP in a CPCCOEt-sensitive manner and was ineffective in crv4/crv4 mouse slices. These observations are relevant to the comprehension of the pathophysiological effects of Tat in central nervous system and may suggest new potential therapeutic approaches to the cure of HIV-1-associated dementia.

Presynaptic Release-Regulating mGlu1 Receptors in Central Nervous System

“…The data demonstrated that the mGlu1/5 receptor agonist facilitated the 12 mM K + -evoked production of endogenous IP 3 and that this facilitation was significantly prevented by CPCCOEt. This is consistent with the participation of the mGlu1-induced signaling in the overproduction of the intraterminal second messenger (Musante et al, 2010). Thus, mGlu1 autoreceptors in mouse cortical nerve endings are positively coupled to an enzymatic pathway leading to IP 3 overproduction and the consequent release of Ca 2+ ions from intraterminal stores.…”

HIV-associated neurocognitive disorder — pathogenesis and prospects for treatment

“…In support of this notion, CSF levels of glutamate are fivefold greater in HIV+ individuals than in healthy controls 137 , and recent studies of HIV+ patients who received CART revealed selective increases in CSF levels of glutamate in patients with HAND compared with patients without neurocognitive impairment 74 . Tat and envelope glycoprotein gp120 have been shown to decrease glial and synaptic glutamate uptake 138,139 , stimulate glutamate release from nerve endings 138,140 , and phosphorylate glutamate receptors, thus potentiating the toxicity of the neurotransmitter 141 . Although glutamate levels in the CSF are increased in HIV+ patients with cognitive impairment, glutamate levels are selectively lower in the parietal grey matter, basal ganglia and cortex 77,78 .…”

An Overview of Human Immunodeficiency Virus Type 1-Associated Common Neurological Complications: Does Aging Pose a Challenge?

“…Tat promotes toxicity by affecting the release of various neurotransmitters. Tat facilitates the exocytosis of excitatory neurotransmitters such as glutamate and NMDA and decreases the release of GABA, an inhibitory neurotransmitter, from the cortex and hippocampal neurons [114, 115]. Furthermore,Tat-mediated glutamate toxicity is exacerbated by phosphorylation of NMDA receptors.…”