title: Up-regulation of the neuronal nicotinic receptor α7 by HIV glycoprotein 120: potential implications for HIV-associated neurocognitive disorder.
abstract: Approximately 30-50% of the >30 million HIV-infected subjects develop neurological complications ranging from mild symptoms to dementia. HIV does not infect neurons, and the molecular mechanisms behind HIV-associated neurocognitive decline are not understood. There are several hypotheses to explain the development of dementia in HIV(+) individuals, including neuroinflammation mediated by infected microglia and neuronal toxicity by HIV proteins. A key protein associated with the neurological complications of HIV, gp120, forms part of the viral envelope and can be found in the CSF of infected individuals. HIV-1-gp120 interacts with several receptors including CD4, CCR5, CXCR4, and nicotinic acetylcholine receptors (nAChRs). However, the role of nAChRs in HIV-associated neurocognitive disorder has not been investigated. We studied the effects of gp120(IIIB) on the expression and function of the nicotinic receptor α7 (α7-nAChR). Our results show that gp120, through activation of the CXCR4 chemokine receptor, induces a functional up-regulation of α7-nAChRs. Because α7-nAChRs have a high permeability to Ca(2+), we performed TUNEL staining to investigate the effects of receptor up-regulation on cell viability. Our data revealed an increase in cell death, which was blocked by the selective antagonist α-bungarotoxin. The in vitro data are supported by RT-PCR and Western blot analysis, confirming a remarkable up-regulation of the α7-nAChR in gp120-transgenic mice brains. Specifically, α7-nAChR up-regulation is observed in mouse striatum, a region severely affected in HIV(+) patients. In summary, CXCR4 activation induces up-regulation of α7-nAChR, causing cell death, suggesting that α7-nAChR is a previously unrecognized contributor to the neurotoxicity associated with HIV infection.
authors.affiliation: Department of Biology, University of Puerto Rico, Río Piedras Campus, San Juan, Puerto Rico.
authors.forename: Leomar Y
authors.initials: LY
authors.lastname: Ballester
authors.forename: Coral M
authors.initials: CM
authors.lastname: Capó-Vélez
authors.forename: Wilfredo F
authors.initials: WF
authors.lastname: García-Beltrán
authors.forename: Félix M
authors.initials: FM
authors.lastname: Ramos
authors.forename: Edwin
authors.initials: E
authors.lastname: Vázquez-Rosa
authors.forename: Raymond
authors.initials: R
authors.lastname: Ríos
authors.forename: José R
authors.initials: JR
authors.lastname: Mercado
authors.forename: Roberto I
authors.initials: RI
authors.lastname: Meléndez
authors.forename: José A
authors.initials: JA
authors.lastname: Lasalde-Dominicci
mesh_terms: D015526:AIDS Dementia Complex / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002038:Bungarotoxins / Q000494:pharmacology; D016923:Cell Death / Q000235:genetics; D003342:Corpus Striatum / Q000378:metabolism* / Q000821:virology; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D002038:Bungarotoxins; C514936:CXCR4 protein, mouse; C579167:Chrna7 protein, human; C579166:Chrna7 protein, mouse; D015699:HIV Envelope Protein gp120; D009419:Nerve Tissue Proteins; D019718:Receptors, CXCR4; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C514793:gp120 protein, Human immunodeficiency virus 1
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