Activation of KCNN3/SK3/KCa2.3 channels attenuates enhanced calcium influx and inflammatory cytokine production in activated microglia

Amalia M. Dolga, Till Letsche, Maike Gold, Nunzianna Doti, Michael Bacher, Nipavan Chiamvimonvat, Richard Dodel, Carsten Culmsee

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

In neurons, small-conductance calcium-activated potassium (KCNN/SK/KCa2) channels maintain calcium homeostasis after N-methyl-D-aspartate (NMDA) receptor activation, thereby preventing excitotoxic neuronal death. So far, little is known about the function of KCNN/SK/KCa2 channels in non-neuronal cells, such as microglial cells. In this study, we addressed the question whether KCNN/SK/KCa2 channels activation affected inflammatory responses of primary mouse microglial cells upon lipopolysaccharide (LPS) stimulation. We found that N-cyclohexyl-N-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-4-pyrimidinamine (CyPPA), a positive pharmacological activator of KCNN/SK/KCa2 channels, significantly reduced LPS-stimulated activation of microglia in a concentration-dependent manner. The general KCNN/SK/KCa2 channel blocker apamin reverted these effects of CyPPA on microglial proliferation. Since calcium plays a central role in microglial activation, we further addressed whether KCNN/SK/KCa2 channel activation affected the changes of intracellular calcium levels, [Ca2+]i,, in microglial cells. Our data show that LPS-induced elevation of [Ca2+]i was attenuated following activation of KCNN2/3/KCa2.2/KCa2.3 channels by CyPPA. Furthermore, CyPPA reduced downstream events including tumor necrosis factor alpha and interleukin 6 cytokine production and nitric oxide release in activated microglia. Further, we applied specific peptide inhibitors of the KCNN/SK/KCa2 channel subtypes to identify which particular channel subtype mediated the observed anti-inflammatory effects. Only inhibitory peptides targeting KCNN3/SK3/KCa2.3 channels, but not KCNN2/SK2/KCa2.2 channel inhibition, reversed the CyPPA-effects on LPS-induced microglial proliferation. These findings revealed that KCNN3/SK3/KCa2.3 channels can modulate the LPS-induced inflammatory responses in microglial cells. Thus, KCNN3/SK3/KCa2.3 channels may serve as a therapeutic target for reducing microglial activity and related inflammatory responses in the central nervous system.

Original languageEnglish (US)
Pages (from-to)2050-2064
Number of pages15
JournalGLIA
Volume60
Issue number12
DOIs
StatePublished - Dec 2012

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Keywords

  • Calcium homeostasis
  • CyPPA
  • Cytokines
  • Microglia
  • Potassium KCNN/SK/K2 channels

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Neurology

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