Nature Neuroscience
- 9, 1512 - 1519 (2006)
Published online: 19 November 2006; | doi:10.1038/nn1805
The P2Y12 receptor regulates microglial activation by extracellular nucleotidesSharon E Haynes1, Gunther Hollopeter1, 4, Guang Yang2, Dana Kurpius3, Michael E Dailey3, Wen-Biao Gan2 & David Julius11
Departments of Physiology & Cellular and Molecular Pharmacology, University of California, San Francisco (UCSF), 600 16th Street, San Francisco, California 94158-2517, USA. 2
Department of Physiology and Neuroscience, Skirball Institute Program in Molecular Neurobiology, New York University School of Medicine, 540 First Avenue, New York, New York 10016, USA. 3
Department of Biological Sciences, University of Iowa, 369 Biology Building, Iowa City, Iowa 52242-1324, USA. 4
Present address: Department of Biology, University of Utah, 257 South 1400 East, Salt Lake City, Utah 84112-0840, USA.
Correspondence should be addressed to David Julius julius@cmp.ucsf.edu Microglia are primary immune sentinels of the CNS. Following injury, these cells migrate or extend processes toward sites of tissue damage. CNS injury is accompanied by release of nucleotides, serving as signals for microglial activation or chemotaxis. Microglia express several purinoceptors, including a Gi-coupled subtype that has been implicated in ATP- and ADP-mediated migration in vitro. Here we show that microglia from mice lacking Gi-coupled P2Y12 receptors exhibit normal baseline motility but are unable to polarize, migrate or extend processes toward nucleotides in vitro or in vivo. Microglia in P2ry12
-/- mice show significantly diminished directional branch extension toward sites of cortical damage in the living mouse. Moreover, P2Y12 expression is robust in the 'resting' state, but dramatically reduced after microglial activation. These results imply that P2Y12 is a primary site at which nucleotides act to induce microglial chemotaxis at early stages of the response to local CNS injury.
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