HIV-1 gp120 enhances outward potassium current via CXCR4 and cAMP-dependent protein kinase a signaling in cultured rat microglia

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.