The effects of mGlu1 and mGlu5 receptor activation on the depolarization-evoked release of of both mGlu1 and mGlu5 autoreceptors located presynaptically, while immunocytochemistry revealed their presence at glutamatergic terminals. We propose that mGlu1 and mGlu5
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.
J. Neurochem. (2011) 117, 516–527.
Abstract
Rat hippocampal glutamatergic terminals possess NMDA autoreceptors whose activation by low micromolar NMDA elicits glutamate exocytosis in the presence of physiological Mg2+ (1.2 mM), the release of glutamate being significantly reduced when compared to that in Mg2+‐free condition. Both glutamate and glycine were required to evoke glutamate exocytosis in 1.2 mM Mg2+, while dizocilpine, cis‐4‐[phosphomethyl]‐piperidine‐2‐carboxylic acid and 7‐Cl‐kynurenic acid prevented it, indicating that occupation of both agonist sites is needed for receptor activation. d‐serine mimicked glycine but also inhibited the NMDA/glycine‐induced release of [3H]d‐aspartate, thus behaving as a partial agonist. The NMDA/glycine‐induced release in 1.2 mM Mg2+ strictly depended on glycine uptake through the glycine transporter type 1 (GlyT1), because the GlyT1 blocker N‐[3‐(4′‐fluorophenyl)‐3‐(4′‐phenylphenoxy)propyl])sarcosine hydrochloride, but not the GlyT2 blocker Org 25534, prevented it. Accordingly, [3H]glycine was taken up during superfusion, while lowering the external concentration of Na+, the monovalent cation co‐transported with glycine by GlyT1, abrogated the NMDA‐induced effect. Western blot analysis of subsynaptic fractions confirms that GlyT1 and NMDA autoreceptors co‐localize at the pre‐synaptic level, where GluN3A subunits immunoreactivity was also recovered. It is proposed that GlyT1s coexist with NMDA autoreceptors on rat hippocampal glutamatergic terminals and that glycine taken up by GlyT1 may permit physiological activation of NMDA pre‐synaptic autoreceptors.
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