title: Involvement of Kv1.3 and p38 MAPK signaling in HIV-1 glycoprotein 120-induced microglia neurotoxicity.
abstract: Inflammatory responses mediated by activated microglia play a pivotal role in the pathogenesis of human immunodeficiency virus type 1 (HIV-1)-associated neurocognitive disorders. Studies on identification of specific targets to control microglia activation and resultant neurotoxic activity are imperative. Increasing evidence indicate that voltage-gated K(+) (K(v)) channels are involved in the regulation of microglia functionality. In this study, we investigated K(v)1.3 channels in the regulation of neurotoxic activity mediated by HIV-1 glycoprotein 120 (gp120)-stimulated rat microglia. Our results showed treatment of microglia with gp120 increased the expression levels of K(v)1.3 mRNA and protein. In parallel, whole-cell patch-clamp studies revealed that gp120 enhanced microglia K(v)1.3 current, which was blocked by margatoxin, a K(v)1.3 blocker. The association of gp120 enhancement of K(v)1.3 current with microglia neurotoxicity was demonstrated by experimental results that blocking microglia K(v)1.3 attenuated gp120-associated microglia production of neurotoxins and neurotoxicity. Knockdown of K(v)1.3 gene by transfection of microglia with K(v)1.3-siRNA abrogated gp120-associated microglia neurotoxic activity. Further investigation unraveled an involvement of p38 MAPK in gp120 enhancement of microglia K(v)1.3 expression and resultant neurotoxic activity. These results suggest not only a role K(v)1.3 may have in gp120-associated microglia neurotoxic activity, but also a potential target for the development of therapeutic strategies.
authors.affiliation: Neurophysiology Laboratory, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA.
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.forename: C
authors.initials: C
authors.lastname: Xu
authors.forename: L
authors.initials: L
authors.lastname: Chen
authors.forename: P
authors.initials: P
authors.lastname: Xu
authors.forename: H
authors.initials: H
authors.lastname: Xiong
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D020868:Gene Silencing; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017628:Microglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009498:Neurotoxins / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012604:Scorpion Venoms / Q000494:pharmacology; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D015699:HIV Envelope Protein gp120; D051664:Kv1.3 Potassium Channel; D009498:Neurotoxins; D026902:Potassium Channel Blockers; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012604:Scorpion Venoms; C077910:margatoxin; D048051:p38 Mitogen-Activated Protein Kinases