title: HIV-1 gp120 enhances outward potassium current via CXCR4 and cAMP-dependent protein kinase A signaling in cultured rat microglia.
abstract: Microglia are critical cells in mediating the pathophysiology of neurodegenerative disorders such as HIV-associated neurocognitive disorders. We hypothesize that HIV-1 glycoprotein 120 (gp120) activates microglia by enhancing outward K(+) currents, resulting in microglia secretion of neurotoxins, consequent neuronal dysfunction, and death. To test this hypothesis, we studied the effects of gp120 on outward K(+) current in cultured rat microglia. Application of gp120 enhanced outward K(+) current in a dose-dependent manner, which was blocked by voltage-gated K(+) (K(v) ) channel blockers. Western blot analysis revealed that gp120 produced an elevated expression of K(v) channel proteins. Examination of activation and inactivation of outward K(+) currents showed that gp120 shifted membrane potentials for activation and steady-state inactivation. The gp120-associated enhancement of outward K(+) current was blocked by either a CXCR4 receptor antagonist T140 or a specific protein kinase A (PKA) inhibitor H89, suggesting the involvement of chemokine receptor CXCR4 and PKA in gp120-mediated enhancement of outward K(+) current. Biological significance of gp120-induced enhancement of microglia outward K(+) current was demonstrated by experimental results showing the neurotoxic activity of gp120-stimulated microglia, evaluated by TUNEL staining and MTT assay, significantly attenuated by K(v) channel blockers. Taken together, these results suggest that gp120 induces microglia neurotoxic activity by enhancing microglia outward K(+) current and that microglia K(v) channels may function as a potential target for the development of therapeutic strategies.
authors: Neurophysiology Laboratory, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors: Changshui
authors: C
authors: Xu
authors: Jianuo
authors: J
authors: Liu
authors: Lina
authors: L
authors: Chen
authors: Shangdong
authors: S
authors: Liang
authors: Nobutaka
authors: N
authors: Fujii
authors: Hirokazu
authors: H
authors: Tamamura
authors: Huangui
authors: H
authors: Xiong
mesh_terms: D015526:AIDS Dementia Complex / Q000201:enzymology / Q000378:metabolism / Q000821:virology; D000818:Animals; D002478:Cells, Cultured; D018920:Coculture Techniques; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D015699:HIV Envelope Protein gp120 / Q000502:physiology*; D008564:Membrane Potentials / Q000502:physiology; D017628:Microglia / Q000201:enzymology / Q000378:metabolism* / Q000821:virology*; D009410:Nerve Degeneration / Q000201:enzymology / Q000378:metabolism / Q000821:virology; D015221:Potassium Channels / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019718:Receptors, CXCR4 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C486264:Cxcr4 protein, rat; D015699:HIV Envelope Protein gp120; D015221:Potassium Channels; D019718:Receptors, CXCR4; C514793:gp120 protein, Human immunodeficiency virus 1; D017868:Cyclic AMP-Dependent Protein Kinases