Role of Na+/H+ exchangers, excitatory amino acid receptors and voltage-operated Ca2+ channels in human immunodeficiency virus type 1 gp 120-mediated increases in intracellular Ca2+ in human neurons and astrocytes

C. P. Holden, N. J. Haughey, A. Nath, J. D. Geiger

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Abstract

Human immunodeficiency virus type 1 (HIV-1) dementia is the commonest form of dementia in North American people less than 60 years of age. HIV-1 envelope glycoprotein gp120 has been implicated in the neurotoxicity observed in, and the pathogenesis of, HIV-1 dementia. Recombinant gp120 (gp120) was pressure-applied on to cultured human fetal neurons and astrocytes and, by using single-cell calcium imaging, we determined the mechanisms responsible for gp120-induced increases in the levels of intracellular calcium ([Ca2+](i)). Significant dose-related increases in [Ca2+](i) were observed in neurons and astrocytes. In neurons, 5 pM gp120 increased [Ca2+](i) by 290 ± 13 nM and increases of 2210 ± 211 nM were found at 209 nM, the highest concentration of gp120 tested. The apparent EC50 value for gp120 of 223 ± 40 pM in neurons was not significantly different from that in astrocytes. Immunoelution of gp120 with polyclonal anti-gp120 and Ca2+- free conditions blocked increases in [Ca2+](i) by gp120. Increases in [Ca2+](i) were significantly (P < 0.005) attenuated by the Na+/H+ exchange blocker 5-(N-methyl-N-isobutyl)-amiloride in neurons and astrocytes. The L-type calcium channel blockers nimodipine, diltiazem and CdCl2 + NiCl2 significantly (P < 0.005) reduced increases in [Ca2+](i) in neurons, but not astrocytes. Increases in [Ca2+](i) by gp120 were not significantly affected by blockers of N-, P- and Q-type calcium channels. The N-methyl-D- aspartate receptor antagonists (±)-2-amino-5-phosphonopentanoic acid (AP5), memantine and dizocilpine significantly (P < 0.01) lowered gp120-induced increases in [Ca2+](i) in neurons. AP5 and memantine, but not dizocilpine, significantly (P < 0.01) reduced increases in [Ca2+]i by gp120 in astrocytes. Gp120 appears to activate astrocyte Na+/H+ exchangers to release glutamate and potassium and, subsequent to this, increases in [Ca2+](i) in neurons and astrocytes result from activation of excitatory amino acid receptors on astrocytes and neurons, and voltage-operated calcium channels on neurons. Drugs that block gp120-induced changes in [Ca2+](i) in neurons and astrocytes may help in the treatment of HIV-1 dementia.

Original languageEnglish (US)
Pages (from-to)1369-1378
Number of pages10
JournalNeuroscience
Volume91
Issue number4
DOIs
StatePublished - Jul 1 1999

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Sodium-Hydrogen Antiporter
Glutamate Receptors
Astrocytes
HIV-1
Neurons
Dementia
Memantine
Dizocilpine Maleate
Q-Type Calcium Channels
P-Type Calcium Channels
Calcium
Aminoacylation
2-Amino-5-phosphonovalerate
Cadmium Chloride
L-Type Calcium Channels
Nimodipine
Diltiazem
Calcium Channel Blockers
Calcium Channels
N-Methyl-D-Aspartate Receptors

Keywords

  • Calcium channels
  • Excitatory amino acid receptors
  • Human immunodeficiency virus type 1 envelope glycoprotein 120
  • Human neurons and astrocytes
  • Intracellular calcium
  • Sodium-hydrogen exchangers

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

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title = "Role of Na+/H+ exchangers, excitatory amino acid receptors and voltage-operated Ca2+ channels in human immunodeficiency virus type 1 gp 120-mediated increases in intracellular Ca2+ in human neurons and astrocytes",
abstract = "Human immunodeficiency virus type 1 (HIV-1) dementia is the commonest form of dementia in North American people less than 60 years of age. HIV-1 envelope glycoprotein gp120 has been implicated in the neurotoxicity observed in, and the pathogenesis of, HIV-1 dementia. Recombinant gp120 (gp120) was pressure-applied on to cultured human fetal neurons and astrocytes and, by using single-cell calcium imaging, we determined the mechanisms responsible for gp120-induced increases in the levels of intracellular calcium ([Ca2+](i)). Significant dose-related increases in [Ca2+](i) were observed in neurons and astrocytes. In neurons, 5 pM gp120 increased [Ca2+](i) by 290 ± 13 nM and increases of 2210 ± 211 nM were found at 209 nM, the highest concentration of gp120 tested. The apparent EC50 value for gp120 of 223 ± 40 pM in neurons was not significantly different from that in astrocytes. Immunoelution of gp120 with polyclonal anti-gp120 and Ca2+- free conditions blocked increases in [Ca2+](i) by gp120. Increases in [Ca2+](i) were significantly (P < 0.005) attenuated by the Na+/H+ exchange blocker 5-(N-methyl-N-isobutyl)-amiloride in neurons and astrocytes. The L-type calcium channel blockers nimodipine, diltiazem and CdCl2 + NiCl2 significantly (P < 0.005) reduced increases in [Ca2+](i) in neurons, but not astrocytes. Increases in [Ca2+](i) by gp120 were not significantly affected by blockers of N-, P- and Q-type calcium channels. The N-methyl-D- aspartate receptor antagonists (±)-2-amino-5-phosphonopentanoic acid (AP5), memantine and dizocilpine significantly (P < 0.01) lowered gp120-induced increases in [Ca2+](i) in neurons. AP5 and memantine, but not dizocilpine, significantly (P < 0.01) reduced increases in [Ca2+]i by gp120 in astrocytes. Gp120 appears to activate astrocyte Na+/H+ exchangers to release glutamate and potassium and, subsequent to this, increases in [Ca2+](i) in neurons and astrocytes result from activation of excitatory amino acid receptors on astrocytes and neurons, and voltage-operated calcium channels on neurons. Drugs that block gp120-induced changes in [Ca2+](i) in neurons and astrocytes may help in the treatment of HIV-1 dementia.",
keywords = "Calcium channels, Excitatory amino acid receptors, Human immunodeficiency virus type 1 envelope glycoprotein 120, Human neurons and astrocytes, Intracellular calcium, Sodium-hydrogen exchangers",
author = "Holden, {C. P.} and Haughey, {N. J.} and A. Nath and Geiger, {J. D.}",
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T1 - Role of Na+/H+ exchangers, excitatory amino acid receptors and voltage-operated Ca2+ channels in human immunodeficiency virus type 1 gp 120-mediated increases in intracellular Ca2+ in human neurons and astrocytes

AU - Holden, C. P.

AU - Haughey, N. J.

AU - Nath, A.

AU - Geiger, J. D.

PY - 1999/7/1

Y1 - 1999/7/1

N2 - Human immunodeficiency virus type 1 (HIV-1) dementia is the commonest form of dementia in North American people less than 60 years of age. HIV-1 envelope glycoprotein gp120 has been implicated in the neurotoxicity observed in, and the pathogenesis of, HIV-1 dementia. Recombinant gp120 (gp120) was pressure-applied on to cultured human fetal neurons and astrocytes and, by using single-cell calcium imaging, we determined the mechanisms responsible for gp120-induced increases in the levels of intracellular calcium ([Ca2+](i)). Significant dose-related increases in [Ca2+](i) were observed in neurons and astrocytes. In neurons, 5 pM gp120 increased [Ca2+](i) by 290 ± 13 nM and increases of 2210 ± 211 nM were found at 209 nM, the highest concentration of gp120 tested. The apparent EC50 value for gp120 of 223 ± 40 pM in neurons was not significantly different from that in astrocytes. Immunoelution of gp120 with polyclonal anti-gp120 and Ca2+- free conditions blocked increases in [Ca2+](i) by gp120. Increases in [Ca2+](i) were significantly (P < 0.005) attenuated by the Na+/H+ exchange blocker 5-(N-methyl-N-isobutyl)-amiloride in neurons and astrocytes. The L-type calcium channel blockers nimodipine, diltiazem and CdCl2 + NiCl2 significantly (P < 0.005) reduced increases in [Ca2+](i) in neurons, but not astrocytes. Increases in [Ca2+](i) by gp120 were not significantly affected by blockers of N-, P- and Q-type calcium channels. The N-methyl-D- aspartate receptor antagonists (±)-2-amino-5-phosphonopentanoic acid (AP5), memantine and dizocilpine significantly (P < 0.01) lowered gp120-induced increases in [Ca2+](i) in neurons. AP5 and memantine, but not dizocilpine, significantly (P < 0.01) reduced increases in [Ca2+]i by gp120 in astrocytes. Gp120 appears to activate astrocyte Na+/H+ exchangers to release glutamate and potassium and, subsequent to this, increases in [Ca2+](i) in neurons and astrocytes result from activation of excitatory amino acid receptors on astrocytes and neurons, and voltage-operated calcium channels on neurons. Drugs that block gp120-induced changes in [Ca2+](i) in neurons and astrocytes may help in the treatment of HIV-1 dementia.

AB - Human immunodeficiency virus type 1 (HIV-1) dementia is the commonest form of dementia in North American people less than 60 years of age. HIV-1 envelope glycoprotein gp120 has been implicated in the neurotoxicity observed in, and the pathogenesis of, HIV-1 dementia. Recombinant gp120 (gp120) was pressure-applied on to cultured human fetal neurons and astrocytes and, by using single-cell calcium imaging, we determined the mechanisms responsible for gp120-induced increases in the levels of intracellular calcium ([Ca2+](i)). Significant dose-related increases in [Ca2+](i) were observed in neurons and astrocytes. In neurons, 5 pM gp120 increased [Ca2+](i) by 290 ± 13 nM and increases of 2210 ± 211 nM were found at 209 nM, the highest concentration of gp120 tested. The apparent EC50 value for gp120 of 223 ± 40 pM in neurons was not significantly different from that in astrocytes. Immunoelution of gp120 with polyclonal anti-gp120 and Ca2+- free conditions blocked increases in [Ca2+](i) by gp120. Increases in [Ca2+](i) were significantly (P < 0.005) attenuated by the Na+/H+ exchange blocker 5-(N-methyl-N-isobutyl)-amiloride in neurons and astrocytes. The L-type calcium channel blockers nimodipine, diltiazem and CdCl2 + NiCl2 significantly (P < 0.005) reduced increases in [Ca2+](i) in neurons, but not astrocytes. Increases in [Ca2+](i) by gp120 were not significantly affected by blockers of N-, P- and Q-type calcium channels. The N-methyl-D- aspartate receptor antagonists (±)-2-amino-5-phosphonopentanoic acid (AP5), memantine and dizocilpine significantly (P < 0.01) lowered gp120-induced increases in [Ca2+](i) in neurons. AP5 and memantine, but not dizocilpine, significantly (P < 0.01) reduced increases in [Ca2+]i by gp120 in astrocytes. Gp120 appears to activate astrocyte Na+/H+ exchangers to release glutamate and potassium and, subsequent to this, increases in [Ca2+](i) in neurons and astrocytes result from activation of excitatory amino acid receptors on astrocytes and neurons, and voltage-operated calcium channels on neurons. Drugs that block gp120-induced changes in [Ca2+](i) in neurons and astrocytes may help in the treatment of HIV-1 dementia.

KW - Calcium channels

KW - Excitatory amino acid receptors

KW - Human immunodeficiency virus type 1 envelope glycoprotein 120

KW - Human neurons and astrocytes

KW - Intracellular calcium

KW - Sodium-hydrogen exchangers

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U2 - 10.1016/S0306-4522(98)00714-3

DO - 10.1016/S0306-4522(98)00714-3

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