Differential Kv1.3, KCa3.1, and Kir2.1 expression in “classically” and “alternatively” activated microglia

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• 作者：Hai M. Nguyen ; Eva M. Gr&ouml ; ssinger ; Makoto Horiuchi ; Kyle W. Davis ; Lee-Way Jin ; Izumi Maezawa and Heike Wulff
• 刊名：Glia
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：65
• 期：1
• 页码：106-121
• 全文大小：1387K
• ISSN：1098-1136

文摘

Microglia are highly plastic cells that can assume different phenotypes in response to microenvironmental signals. Lipopolysaccharide (LPS) and interferon-γ (IFN-γ) 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_V1.3 blockers PAP-1 and ShK-186, an inwardly rectifying Ba²⁺-sensitive K_ir2.1 current, and a Ca²⁺-activated, TRAM-34-sensitive K_Ca3.1 current. Both K_V1.3 and K_Ca3.1 blockers inhibited pro-inflammatory cytokine production and iNOS and COX2 expression demonstrating that K_V1.3 and K_Ca3.1 play important roles in microglia activation. Following differentiation with LPS or a combination of LPS and IFN-γ microglia exhibited high K_V1.3 current densities (∼50 pA/pF at 40 mV) and virtually no K_Ca3.1 and K_ir currents, while microglia differentiated with IL-4 exhibited large K_ir2.1 currents (∼ 10 pA/pF at −120 mV). K_Ca3.1 currents were generally low but moderately increased following stimulation with IFN-γ or ATP (∼10 pS/pF). This differential K⁺ channel expression pattern suggests that K_V1.3 and K_Ca3.1 inhibitors could be used to inhibit detrimental neuroinflammatory microglia functions. GLIA 2016;65:106–121