title: Target of HIV-1 Envelope Glycoprotein gp120-Induced Hippocampal Neuron Damage: Role of Voltage-Gated K(+) Channel Kv2.1.
abstract: Human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein 120 (gp120) has been reported to be toxic to the hippocampal neurons, and to be involved in the pathogenesis of HIV-1-associated neurocognitive disorders (HAND). Accumulating evidence has demonstrated that voltage-gated potassium (Kv) channels, especially the outward delayed-rectifier K(+) (Ik) channels, play a critical role in gp120-induced cortical neuronal death in vitro. However, the potential mechanisms underlying the hippocampal neuronal injury resulted from gp120-mediated neurotoxicity remain poorly understood. Using whole-cell patch clamp recording in cultured hippocampal neurons, this study found that gp120 significantly increased the outward delayed-rectifier K(+) currents (Ik). Meanwhile, Western blot assay revealed that gp120 markedly upregulated Kv2.1 protein levels, which was consistent with the increased Ik density. With Western blot and terminal deoxynucleotidyl transferase dUTP nick end labeling assays, it was discovered that gp120-induced neuronal injury was largely due to activation of Kv2.1 channels and resultant apoptosis mediated by caspase-3 activation, as the pharmacological blockade of Kv2.1 channels largely attenuated gp120-induced cell damage and caspase-3 expression. Moreover, p38 MAPK was demonstrated to participate in gp120-induced hippocampal neural damage, since p38 MAPK antagonist (SB203580) partially abrogated gp120-induced Kv2.1 upregulation and neural apoptosis. Taken together, these results suggest that gp120 induces hippocampal neuron apoptosis by enhancement of the Ik, which might be associated with increased Kv2.1 expression via the p38 MAPK pathway.
authors.affiliation: 1 Key Lab of Modern Toxicology (NJMU), Ministry of Education, Department of Toxicology, School of Public Health, Nanjing Medical University , Nanjing, China .
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhu
authors.affiliation: 1 Key Lab of Modern Toxicology (NJMU), Ministry of Education, Department of Toxicology, School of Public Health, Nanjing Medical University , Nanjing, China .
authors.forename: Xu
authors.initials: X
authors.lastname: Song
authors.affiliation: 1 Key Lab of Modern Toxicology (NJMU), Ministry of Education, Department of Toxicology, School of Public Health, Nanjing Medical University , Nanjing, China .
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.affiliation: 1 Key Lab of Modern Toxicology (NJMU), Ministry of Education, Department of Toxicology, School of Public Health, Nanjing Medical University , Nanjing, China .
authors.forename: Yixin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 2 Department of Psychology, Queens College, City University of New York , New York.
authors.forename: Jianxun
authors.initials: J
authors.lastname: Xia
authors.affiliation: 1 Key Lab of Modern Toxicology (NJMU), Ministry of Education, Department of Toxicology, School of Public Health, Nanjing Medical University , Nanjing, China .
authors.forename: Wenyi
authors.initials: W
authors.lastname: Qian
authors.affiliation: 1 Key Lab of Modern Toxicology (NJMU), Ministry of Education, Department of Toxicology, School of Public Health, Nanjing Medical University , Nanjing, China .
authors.forename: Jingying
authors.initials: J
authors.lastname: Zhu
authors.affiliation: 1 Key Lab of Modern Toxicology (NJMU), Ministry of Education, Department of Toxicology, School of Public Health, Nanjing Medical University , Nanjing, China .
authors.forename: Rong
authors.initials: R
authors.lastname: Gao
authors.affiliation: 1 Key Lab of Modern Toxicology (NJMU), Ministry of Education, Department of Toxicology, School of Public Health, Nanjing Medical University , Nanjing, China .
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: 1 Key Lab of Modern Toxicology (NJMU), Ministry of Education, Department of Toxicology, School of Public Health, Nanjing Medical University , Nanjing, China .
authors.forename: Hang
authors.initials: H
authors.lastname: Xiao
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002478:Cells, Cultured; D005260:Female; D015699:HIV Envelope Protein gp120 / Q000633:toxicity*; D015497:HIV-1 / Q000472:pathogenicity*; D020935:MAP Kinase Signaling System; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D017207:Rats, Sprague-Dawley; D051669:Shab Potassium Channels / Q000096:biosynthesis*; D015854:Up-Regulation
chemical_list: D015699:HIV Envelope Protein gp120; C496991:Kcnb1 protein, rat; D051669:Shab Potassium Channels; C514793:gp120 protein, Human immunodeficiency virus 1