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Microglial zinc uptake via zinc transporters induces ATP release and the activation of microglia
Author(s) -
Higashi Youichirou,
Segawa Shohei,
Matsuo Takaaki,
Nakamura Shogo,
Kikkawa Yukiko,
Nishida Kentaro,
Nagasawa Kazuki
Publication year - 2011
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.21235
Subject(s) - microglia , nadph oxidase , extracellular , zinc , biochemistry , reactive oxygen species , chemistry , biology , microbiology and biotechnology , biophysics , immunology , inflammation , organic chemistry
Previously, we demonstrated that extracellular zinc plays a key role in transient global ischemia‐induced microglial activation through sequential activation of NADPH oxidase and poly(ADP‐ribose) polymerase (PARP)‐1. However, it remains unclear how zinc causes the sequential activation of microglia. Here, we examined whether transporter‐mediated zinc uptake is necessary for microglial activation. Administration of zinc to microglia activated them through reactive oxygen species (ROS) generation and poly(ADP‐ribose) (PAR) formation, which were suppressed by intracellular zinc chelation with 25 μM TPEN ( N , N , N ′, N ′‐tetrakis(2‐pyridylmethyl)ethylenediamine) or 2 μM BAPTA‐AM (1,2‐bis(2‐aminophenoxy)ethane‐ N , N , N ′, N ′‐tetraacetic acid‐acetoxymethyl ester). The 65 Zn uptake by microglia was temperature‐ and dose‐dependent, and it was blocked by metal cations, but not by L‐type calcium channel blockers nifedipine and nimodipine. Expression of Zrt‐Irt‐like protein (ZIP)1, a plasma membrane‐type zinc transporter, was detected in microglia, and nickel, a relatively sensitive substrate/inhibitor of ZIP1, showed cis ‐ and trans ‐inhibitory effects on the 65 Zn uptake. Exposure of microglia to zinc increased the extracellular ATP concentration, which was suppressed by intracellular zinc chelation and inhibition of hemichannels. mRNA expression of several types of P2 receptors was detected in microglia, and periodate‐oxidized ATP, a selective P2×7 receptor antagonist, attenuated the zinc‐induced microglial activation via NADPH oxidase and PARP‐1. Exogenous ATP and 2′(3′)‐ O ‐(4‐benzoyl‐benzoyl) ATP also caused microglial activation through ROS generation and PAR formation. These findings demonstrate that ZIP1‐mediated uptake of zinc induces ATP release and autocrine/paracrine activation of P2X(7) receptors, and then activates microglia, suggesting that zinc transporter‐mediated uptake of zinc is a trigger for microglial activation via the NADPH oxidase and PARP‐1 pathway. © 2011 Wiley‐Liss, Inc.