The Envelope Glycoprotein of HIV‐1 Alters NMDA Receptor Function

Pm, Sweetnam; Oh, Saab; Jt, Wroblewski; Ce, Price; Ew, Karbon; Jw, Ferkany

doi:10.1111/j.1460-9568.1993.tb00494.x

Cited by 21 publications

(11 citation statements)

References 32 publications

(41 reference statements)

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“…HIV gp120 has been reported to have CD4-independent effects on rat neurons that may be mediated through the N-methyl-D-aspartate (NMDA) receptor (10,41). Drugs that either deplete (caffeine, thapsigargin) or block release from (dantrolene) intracellular Ca 2ϩ stores were effective in blocking the rise in intracellular Ca 2ϩ and cell death in rat neural tissue caused by gp120 (34).…”

Section: Discussionmentioning

confidence: 91%

p38 MAP kinase-mediated negative inotropic effect of HIV gp120 on cardiac myocytes

Kan

Xie²,

Finkel³

2004

American Journal of Physiology-Cell Physiology

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Kan, Hong, Zirong Xie, and Mitchell S. Finkel. p38 MAP kinase-mediated negative inotropic effect of HIV gp120 on cardiac myocytes. Am J Physiol Cell Physiol 286: C1-C7, 2004; 10.1152/ ajpcell.00059.2003.-Myocardial dysfunction leading to dilated cardiomyopathy has been documented with surprisingly high frequency in human immunodeficiency virus (HIV)-infected individuals. p38 MAP kinase has been implicated as a mediator of myocardial dysfunction. We previously reported p38 MAP kinase activation by the HIV coat protein gp120 in neonatal rat cardiac myocytes. We now report the direct inotropic effects of HIV gp120 on adult rat ventricular myocytes (ARVM). ARVM were continuously superfused with gp120, and percent fractional shortening (FS) was determined by automated border detection and simultaneous intracellular ionized free Ca 2ϩ concentration ([Ca 2ϩ ]i) measured by fura 2-AM fluorescence: gp120 alone increased FS and increased [Ca 2ϩ ]i within 5 min and then depressed FS without a decrease in [Ca 2ϩ ]i by 20-60 min, which persisted for at least 2 h. Exposure of ARVM to gp120 also resulted in the phosphorylation of the upstream regulator of p38 MAP kinase MKK3/6, p38 MAP kinase itself, and its downstream effector, ATF-2, over a similar time course. ERK (p44/42) and JNK stress signaling pathways were not similarly activated. The effects of the p38 MAP kinase inhibitor were concentration dependent. SB-203580 (10 M) blocked both p38 MAP kinase phosphorylation and the delayed negative inotropic effect of gp120. SB-203580 (5 M) selectively blocked phosphorylation of ATF-2 without blocking the phosphorylation of MKK3/6 or p38 MAP kinase itself. SB-203580 (5 M) administered before, with, or after gp120 blocked the negative inotropic effect of gp120 in ARVM. p38 MAP kinase activation may be a common stress-response mechanism contributing to myocardial dysfunction in HIV and other nonischemic as well as ischemic cardiomyopathies.

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Section: Discussionmentioning

confidence: 91%

p38 MAP kinase-mediated negative inotropic effect of HIV gp120 on cardiac myocytes

Kan

Xie²,

Finkel³

2004

American Journal of Physiology-Cell Physiology

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“…Gp120 binds with high affinity to CD4 receptor positive T-lymphocytes resulting in severe CD4 ? T-lymphocyte depletion [1,5,20,[30][31][32]. The binding of gp120 to CD4 ?…”

Section: Discussionmentioning

confidence: 99%

“…The binding of gp120 to CD4 ? T lymphocytes and chemokine co-receptors (CCR5, CXCR4) has been well established [1,5,20,[30][31][32]. Gp120/CXCR4-mediated critical cell biological events include neuronal and endothelial cell injury associated with increased intracellular calcium levels and protein phosphorylation [7,25].…”

Section: Discussionmentioning

confidence: 99%

CXCR4 Receptor Antagonist Blocks Cardiac Myocyte P38 MAP Kinase Phosphorylation by HIV gp120

et al. 2008

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The prognosis for patients with human immunodeficiency virus (HIV) infection has improved remarkably as a result of effective antiretroviral therapy. This has resulted in an increased awareness of cardiac complications from HIV infection, including cardiomyopathy and overt heart failure. Mechanisms responsible for HIV cardiomyopathy and heart failure are unknown, but may include direct effects of HIV proteins on the heart. We have previously reported that the HIV envelope glycoprotein, gp120, has a p38 MAP kinase-dependent negative inotropic effect on adult rat ventricular myocytes (ARVM). This signaling pathway presumably results from the binding of gp120 to a specific receptor on the surface of cardiac myocytes. HIV gp120 has been shown to bind to CD4, CXCR4, and CCR5 receptors on lymphocytes and macrophages. Accordingly, we sought to determine if HIV gp120 regulated its negative inotropic effect through activation of one of these binding sites on cardiac myocytes. AMD3100, a highly selective CXCR4 receptor antagonist, reversed HIV gp120-induced negative inotropic effect on ARVM. AMD3100 also blocked HIV gp120 phosphorylation of both p38 MAP kinase and Troponin I. The binding of gp120 to the CXCR4 receptor on ARVM was confirmed by co-immunoprecipitation. We conclude that the negative inotropic effect of HIV gp120 is mediated by a novel signaling pathway that begins with binding to a cardiac myocyte CXCR4 receptor, followed by phosphorylation of both p38 MAP kinase and Troponin I.

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“…For example, PAF neurotoxicity is mediated by two pathways, one dependent and the other independent of the NMDA receptor (Clark et al, 1992;Gelbard et al, 1994). Also, arachidonate metabolites and gp120 can augment NMDA receptor activity (Sweetman et al, 1993;Horimoto et al, 1996;Fontana et al, 1997).…”

Section: Mechanisms Of Quin Toxicitymentioning

confidence: 99%

Involvement of quinolinic acid in aids dementia complex

2005

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Human immunodeficiency virus (HIV) infection is often complicated by the development of acquired immunodeficiency syndrome (AIDS) dementia complex (ADC). Quinolinic acid (QUIN) is an end product of tryptophan, metabolized through the kynurenine pathway (KP) that can act as an endogenous brain excitotoxin when produced and released by activated macrophages/microglia, the very cells that are prominent in the pathogenesis of ADC. This review examines QUIN's involvement in the features of ADC and its role in pathogenesis. We then synthesize these findings into a hypothetical model for the role played by QUIN in ADC, and discuss the implications of this model for ADC and other inflammatory brain diseases.

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The Envelope Glycoprotein of HIV‐1 Alters NMDA Receptor Function

Cited by 21 publications

References 32 publications

p38 MAP kinase-mediated negative inotropic effect of HIV gp120 on cardiac myocytes

p38 MAP kinase-mediated negative inotropic effect of HIV gp120 on cardiac myocytes

CXCR4 Receptor Antagonist Blocks Cardiac Myocyte P38 MAP Kinase Phosphorylation by HIV gp120

Involvement of quinolinic acid in aids dementia complex

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