HIV gp120 upregulates tonic inhibition through α5-containing GABAA Rs

Neuropharmacology
Matthew V Green, Stanley A Thayer

Abstract

HIV-Associated Neurocognitive disorder (HAND) affects nearly half of infected patients. The HIV envelope protein gp120 is shed by infected cells and is a potent neurotoxin in vitro that reproduces many aspects of HAND when expressed in vivo. Here, we show that HIV gp120 increases the amplitude of a tonic current mediated by γ-aminobutyric acid type-A receptors (GABAARs). Treating rat hippocampal cultures with 600 pM gp120IIIB for 4 h increased a tonic bicuculline-sensitive current, which remained elevated for 24 h. The increased current resulted from upregulation of extrasynaptic α5-containing GABAARs, as indicated by inhibition with the selective inverse agonist basmisanil. Treatment with gp120 increased α5-GABAAR immunoreactivity on the cell surface without new protein synthesis. The increase in tonic inhibition was prevented by a C-X-C chemokine receptor type 4 (CXCR4) antagonist or elimination of microglia from the culture. Treatment with interleukin-1β (IL-1β) increased the tonic current and an IL-1 receptor antagonist blocked the gp120-evoked response. Pharmacological or genetic inhibition of p38 mitogen-activated protein kinase (MAPK) prevented the gp120-evoked increase in tonic current and direct activation of a mutant ...Continue Reading

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Citations

Mar 24, 2020·Expert Opinion on Therapeutic Patents·Letizia Crocetti, Gabriella Guerrini
Feb 16, 2021·Cellular and Molecular Life Sciences : CMLS·Elena IrolloOlimpia Meucci

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