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Involvement of P2X4 and P2Y12 receptors in ATP-induced microglial chemotaxis

Keiko Ohsawa1, Yasuhiro Irino, Yasuko Nakamura

  • 1Department of Neurochemistry, National Institute of Neuroscience, Kodaira, Tokyo 187-8502, Japan.

Glia
|February 15, 2007
PubMed

Insights

Extracellular ATP triggers microglial movement via P2Y12 receptors and phosphatidylinositol 3-kinase (PI3K) signaling. The P2X4 receptor also plays a crucial role in this ATP-induced microglial chemotaxis.

Area of Science:

  • Neuroscience
  • Immunology
  • Cell Biology

Background:

  • Extracellular ATP is known to induce microglial responses like membrane ruffling and chemotaxis.
  • The Gi/o-protein coupled P2Y12 receptor (P2Y12R) was previously suggested to mediate these ATP-induced microglial behaviors.

Purpose of the Study:

  • To elucidate the intracellular signaling pathway downstream of P2Y12R involved in ATP-induced microglial chemotaxis.
  • To investigate the role of the P2X4 receptor (P2X4R) in ATP-induced microglial chemotaxis.

Main Methods:

  • Utilized a Dunn chemotaxis chamber to assess microglial migration.
  • Employed phosphatidylinositol 3-kinase (PI3K) inhibitors (wortmannin, LY294002) and a P2Y12R antagonist.
  • Measured Akt phosphorylation as an indicator of PI3K pathway activation.
  • Investigated the effect of extracellular calcium chelation.
  • Tested P2X4R antagonists and performed P2X4R knockdown using RNA interference via a lentivirus vector system.

Main Results:

  • PI3K inhibitors significantly suppressed microglial chemotaxis but did not affect membrane ruffling.
  • ATP stimulation increased Akt phosphorylation, which was attenuated by PI3K inhibitors and a P2Y12R antagonist, indicating P2Y12R-mediated PI3K pathway activation is essential for chemotaxis.
  • Reduced Akt phosphorylation upon extracellular calcium chelation suggested involvement of ionotropic P2X receptors.
  • Pharmacological blockade and knockdown of P2X4R significantly inhibited ATP-induced microglial chemotaxis.

Conclusions:

  • P2Y12R-mediated activation of the PI3K/Akt pathway is critical for ATP-induced microglial chemotaxis.
  • The ionotropic P2X4R is also significantly involved in ATP-induced microglial chemotaxis.
  • Both P2Y12R and P2X4R contribute to the microglial chemotactic response to extracellular ATP.

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