期刊
GLIA
卷 65, 期 1, 页码 106-121出版社
WILEY-BLACKWELL
DOI: 10.1002/glia.23078
关键词
microglia; potassium channel; Kv1.3; KCa3.1; Kir2.1; TRAM-34; PAP-1
资金
- National Institute of Neurological Disease and Stroke Award [NS098328]
- National Institute on Aging Award [AG043788]
Microglia are highly plastic cells that can assume different phenotypes in response to microenvironmental signals. Lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) promote differentiation into classically activated M1-like microglia, which produce high levels of pro-inflammatory cytokines and nitric oxide and are thought to contribute to neurological damage in ischemic stroke and Alzheimer's disease. IL-4 in contrast induces a phenotype associated with anti-inflammatory effects and tissue repair. We here investigated whether these microglia subsets vary in their K (+)channel expression by differentiating neonatal mouse microglia into M(LPS) and M(IL-4) microglia and studying their K+ channel expression by whole-cell patch-clamp, quantitative PCR and immunohistochemistry. We identified three major types of K (+)channels based on their biophysical and pharmacological fingerprints: a use-dependent, outwardly rectifying current sensitive to the K(V)1.3 blockers PAP-1 and ShK-186, an inwardly rectifying Ba (2+) -sensitive K(ir)2.1 current, and a Ca (2+) -activated, TRAM-34-sensitive K(Ca)3.1 current. Both K(V)1.3 and K(Ca)3.1 blockers inhibited pro-inflammatory cytokine production and iNOS and COX2 expression demonstrating that K(V)1.3 and K(Ca)3.1 play important roles in microglia activation. Following differentiation with LPS or a combination of LPS and IFN-g microglia exhibited high K(V)1.3 current densities (similar to 50 pA/pF at 40 mV) and virtually no K(Ca)3.1 and Kir currents, while microglia differentiated with IL-4 exhibited large K(ir)2.1 currents (similar to 10 pA/pF at -120 mV). K(Ca)3.1 currents were generally low but moderately increased following stimulation with IFN-gamma or ATP (similar to 10 pS/pF). This differential K+ channel expression pattern suggests that K(V)1.3 and K(Ca)3.1 inhibitors could be used to inhibit detrimental neuroinflammatory microglia functions.
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