title: Activation of microglial P2Y12 receptor is required for outward potassium currents in response to neuronal injury.
abstract: Microglia, the resident immune cells in the central nervous system (CNS), constantly survey the surrounding neural parenchyma and promptly respond to brain injury. Activation of purinergic receptors such as P2Y12 receptors (P2Y12R) in microglia has been implicated in chemotaxis toward ATP that is released by injured neurons and astrocytes. Activation of microglial P2Y12R elicits outward potassium current that is associated with microglial chemotaxis in response to injury. This study aimed at investigating the identity of the potassium channel implicated in microglial P2Y12R-mediated chemotaxis following neuronal injury and understanding the purinergic signaling pathway coupled to the channel. Using a combination of two-photon imaging, electrophysiology and genetic tools, we found the ATP-induced outward current to be largely dependent on P2Y12R activation and mediated by G-proteins. Similarly, P2Y12R-coupled outward current was also evoked in response to laser-induced single neuron injury. This current was abolished in microglia obtained from mice lacking P2Y12R. Dissecting the properties of the P2Y12R-mediated current using a pharmacological approach revealed that both the ATP and neuronal injury-induced outward current in microglia was sensitive to quinine (1mM) and bupivacaine (400μM), but not tetraethylammonium (TEA) (10mM) and 4-aminopyridine (4-AP) (5mM). These results suggest that the quinine/bupivacaine-sensitive potassium channels are the functional effectors of the P2Y12R-mediated signaling in microglia activation following neuronal injury.
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, United States; Program in Cellular and Molecular Pharmacology, Rutgers University, Piscataway, NJ 08854, United States.
authors.forename: P
authors.initials: P
authors.lastname: Swiatkowski
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, United States.
authors.forename: M
authors.initials: M
authors.lastname: Murugan
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, United States.
authors.forename: U B
authors.initials: UB
authors.lastname: Eyo
authors.affiliation: Stomatological Hospital, Anhui Medical University, Hefei, Anhui 230032, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Neurology, Emory University School of Medicine, 12 Executive Park Drive NE, Atlanta, GA 30329, United States.
authors.forename: S
authors.initials: S
authors.lastname: Rangaraju
authors.affiliation: Department of Neurobiology and Physiology, School of Dentistry, Seoul National University, Seoul, South Korea.
authors.forename: S B
authors.initials: SB
authors.lastname: Oh
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, United States. Electronic address: lwu@dls.rutgers.edu.
authors.forename: L-J
authors.initials: LJ
authors.lastname: Wu
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D002490:Central Nervous System / Q000293:injuries* / Q000378:metabolism; D005260:Female; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism*; D015221:Potassium Channels / Q000378:metabolism*; D058925:Receptors, Purinergic P2Y12 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: C548577:P2ry12 protein, mouse; D015221:Potassium Channels; D058925:Receptors, Purinergic P2Y12; D011188:Potassium
keywords: ATP; K(+) channels; P2Y12 receptor; microglia