Microglial Ramification, Surveillance, and Interleukin-1β Release Are Regulated by the Two-Pore Domain K+ Channel THIK-1

Neuron. 2018 Jan 17;97(2):299-312.e6. doi: 10.1016/j.neuron.2017.12.002. Epub 2017 Dec 28.

Abstract

Microglia exhibit two modes of motility: they constantly extend and retract their processes to survey the brain, but they also send out targeted processes to envelop sites of tissue damage. We now show that these motility modes differ mechanistically. We identify the two-pore domain channel THIK-1 as the main K+ channel expressed in microglia in situ. THIK-1 is tonically active, and its activity is potentiated by P2Y12 receptors. Inhibiting THIK-1 function pharmacologically or by gene knockout depolarizes microglia, which decreases microglial ramification and thus reduces surveillance, whereas blocking P2Y12 receptors does not affect membrane potential, ramification, or surveillance. In contrast, process outgrowth to damaged tissue requires P2Y12 receptor activation but is unaffected by blocking THIK-1. Block of THIK-1 function also inhibits release of the pro-inflammatory cytokine interleukin-1β from activated microglia, consistent with K+ loss being needed for inflammasome assembly. Thus, microglial immune surveillance and cytokine release require THIK-1 channel activity.

Keywords: ATP; THIK-1; inflammasome; interleukin-1β; microglia; potassium channel; ramification; surveillance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / pharmacology
  • Animals
  • Cell Movement
  • Cell Polarity
  • Cell Shape
  • Cell Surface Extensions / physiology
  • Chemotaxis / physiology
  • Inflammasomes / metabolism
  • Interleukin-1beta / physiology*
  • Membrane Potentials
  • Mice
  • Mice, Knockout
  • Microglia / drug effects
  • Microglia / physiology*
  • Potassium / physiology
  • Potassium Channels, Tandem Pore Domain / antagonists & inhibitors
  • Potassium Channels, Tandem Pore Domain / deficiency
  • Potassium Channels, Tandem Pore Domain / physiology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Purinergic P2Y12 / physiology
  • Transcriptome

Substances

  • Inflammasomes
  • Interleukin-1beta
  • Kcnk13 protein, mouse
  • Kcnk13 protein, rat
  • P2ry12 protein, mouse
  • Potassium Channels, Tandem Pore Domain
  • Receptors, Purinergic P2Y12
  • Adenosine Triphosphate
  • Potassium