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

Autor: Nguyen HM; Department of Pharmacology, University of California, Davis, California., Grössinger EM; Department of Pharmacology, University of California, Davis, California., Horiuchi M; Department of Pathology and Laboratory Medicine, University of California Davis Medical Center, Sacramento, California.; M.I.N.D. Institute, University of California Davis Medical Center, Davis, Sacramento, California., Davis KW; Department of Pathology and Laboratory Medicine, University of California Davis Medical Center, Sacramento, California., Jin LW; Department of Pathology and Laboratory Medicine, University of California Davis Medical Center, Sacramento, California.; M.I.N.D. Institute, University of California Davis Medical Center, Davis, Sacramento, California., Maezawa I; Department of Pathology and Laboratory Medicine, University of California Davis Medical Center, Sacramento, California.; M.I.N.D. Institute, University of California Davis Medical Center, Davis, Sacramento, California., Wulff H; Department of Pharmacology, University of California, Davis, California.
Jazyk: angličtina
Zdroj: Glia [Glia] 2017 Jan; Vol. 65 (1), pp. 106-121. Date of Electronic Publication: 2016 Oct 03.
DOI: 10.1002/glia.23078
Abstrakt: 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 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-γ microglia exhibited high K V 1.3 current densities (∼50 pA/pF at 40 mV) and virtually no K Ca 3.1 and K ir currents, while microglia differentiated with IL-4 exhibited large K ir 2.1 currents (∼ 10 pA/pF at -120 mV). K Ca 3.1 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 V 1.3 and K Ca 3.1 inhibitors could be used to inhibit detrimental neuroinflammatory microglia functions. GLIA 2016;65:106-121.
(© 2016 The Authors. Glia Published by Wiley Periodicals, Inc.)
Databáze: MEDLINE
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