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The Journal of Neuroscience, August 3, 2005, 25(31):7139-7149; doi:10.1523/JNEUROSCI.1251-05.2005

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Cellular/Molecular
Microglia Kv1.3 Channels Contribute to Their Ability to Kill Neurons

Christopher B. Fordyce,^1,2 Ravi Jagasia,^1,2 Xiaoping Zhu,¹ and Lyanne C. Schlichter^1,2

¹Division of Cellular and Molecular Biology, Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada M5T 2S8, and ²Department of Physiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8

Many CNS disorders involve an inflammatory response that is orchestrated by cells of the innate immune system: macrophages, neutrophils, and microglia (the endogenous CNS immune cell). Hence, there is considerable interest in anti-inflammatory strategies that target these cells. Microglia express Kv1.3 (KCNA3) channels, which we showed previously are important for their proliferation and the NADPH-mediated respiratory burst. Here, we demonstrate the potential for targeting Kv1.3 channels to control CNS inflammation. Rat microglia express Kv1.2, Kv1.3, and Kv1.5 transcripts and protein, but only a Kv1.3 current was detected. When microglia were activated with lipopolysaccharide or a phorbol ester, only the Kv1.3 transcript (but not protein) expression changed. Using a Transwell cell-culture system that allows separate drug treatment of microglia or neurons, we found that activated microglia killed postnatal hippocampal neurons through a process that requires Kv1.3 channel activity in microglia but not in neurons. A major neurotoxic molecule in this model was peroxynitrite, which is formed from superoxide and nitric oxide; thus, it is significant that Kv1.3 channel blockers reduced the respiratory burst, but not nitric oxide production, by the activated microglia. In addressing the biochemical pathway affected by Kv1.3 channel activity, we found that Kv1.3 acts via a different cellular mechanism from the broad-spectrum drug minocycline, which is often used in animal models of neuroinflammation. That is, the dose-dependent reduction in neuron killing by minocycline corresponded with a reduction in p38 mitogen-activated protein kinase activation in microglia; however, none of the Kv1.3 blockers affected p38 activation.

Key words: microglia activation; neurotoxicity; neuroinflammation; Kv channel roles; Kv expression; anti-inflammatory treatments

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Received March 31, 2005; revised May 19, 2005; accepted June 13, 2005.

This article has been cited by other articles:

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				J. Neumann, S. Sauerzweig, R. Ronicke, F. Gunzer, K. Dinkel, O. Ullrich, M. Gunzer, and K. G. Reymann Microglia Cells Protect Neurons by Direct Engulfment of Invading Neutrophil Granulocytes: A New Mechanism of CNS Immune Privilege J. Neurosci., June 4, 2008; 28(23): 5965 - 5975. [Abstract] [Full Text] [PDF]

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