The P2Y12 receptor regulates microglial activation by extracellular nucleotides.
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 G(i)-coupled subtype that has been implicated in ATP- and ADP-mediated migration in vitro. Here we show that microglia from mice lacking G(i)-coupled P2Y(12) receptors exhibit normal baseline motility but are unable to polarize, migrate or extend processes toward nucleotides in vitro or in vivo. Microglia in P2ry(12)(-/-) mice show significantly diminished directional branch extension toward sites of cortical damage in the living mouse. Moreover, P2Y(12) expression is robust in the 'resting' state, but dramatically reduced after microglial activation. These results imply that P2Y(12) is a primary site at which nucleotides act to induce microglial chemotaxis at early stages of the response to local CNS injury.
Haynes
Sharon E
SE
Department of Physiology & Cellular, University of California, San Francisco (UCSF), 600 16th Street, San Francisco, California 94158-2517, USA.
Hollopeter
Gunther
G
Yang
Guang
G
Kurpius
Dana
D
Dailey
Michael E
ME
Gan
Wen-Biao
WB
Julius
David
D
D000244:Adenosine Diphosphate / Q000378:metabolism / Q000502:physiology; D000255:Adenosine Triphosphate / Q000378:metabolism / Q000502:physiology; D000818:Animals; D001930:Brain Injuries / Q000276:immunology* / Q000378:metabolism; D002490:Central Nervous System / Q000166:cytology / Q000276:immunology; D002633:Chemotaxis / Q000502:physiology*; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000276:immunology / Q000378:metabolism*; D018048:Receptors, Purinergic P2 / Q000276:immunology / Q000378:metabolism*; D058925:Receptors, Purinergic P2Y12
D008565:Membrane Proteins; C548577:P2ry12 protein, mouse; D018048:Receptors, Purinergic P2; D058925:Receptors, Purinergic P2Y12; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate