Activation of NR1a/NR2B receptors by monocyte-derived macrophage secretory products: implications for human immunodeficiency virus type one-associated dementia.
The final pathways for neuronal injury in human immunodeficiency virus type one (HIV-1)-associated dementia (HAD) were investigated in Xenopus oocytes expressing recombinant NR1a/NR2B N-methyl-D-aspartate (NMDA) receptors exposed to secretory products from HIV-infected macrophages. Pressure ejection of HIV-1-infected and CD40 ligand-stimulated human monocyte-derived macrophage (MDM) fluids produced inward currents in oocytes expressing NR1a/NR2B (30.2+/-5.1 nA, n=42, mean+/-SE), but not in uninjected cells. In contrast, control (uninfected MDM) fluids induced currents of 4.5+/-0.5 nA (n=17). Infected or stimulated MDM without virus showed intermediate responses. The induced currents were MDM fluid dose-dependent and blocked by the NMDA receptor antagonist 2-amino-5-phosphonovalerate (50 microM), but not by 6-cyano-7-nitroquinoxaline-2,3-dione (20 microM). Although low levels of glutamate were detected in the culture fluids, the addition of L-glutamate decarboxylase to the MDM did not significantly change the level of induced inward currents. Our experiments demonstrate that secretory factors from HIV-1-infected MDM activate NMDA receptors NR1a/NR2B and may contribute to neuronal demise during HAD.
Xiong
Huangui
H
The Laboratory of Neurophysiology, University of Nebraska Medical Center, Omaha 68198-5215, USA. hxiong@unmc.edu
McCabe
Laura
L
Skifter
Donald
D
Monaghan
Daniel T
DT
Gendelman
Howard E
HE
D015526:AIDS Dementia Complex / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005260:Female; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis
D017077:Culture Media, Conditioned; D016194:Receptors, N-Methyl-D-Aspartate; C121001:NR2B NMDA receptor