{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T06:34:50Z","timestamp":1789972490274,"version":"4.0.1"},"reference-count":78,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2011,8,24]],"date-time":"2011-08-24T00:00:00Z","timestamp":1314144000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Glia"],"published-print":{"date-parts":[[2011,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Previously, we demonstrated that extracellular zinc plays a key role in transient global ischemia\u2010induced microglial activation through sequential activation of NADPH oxidase and poly(ADP\u2010ribose) polymerase (PARP)\u20101. However, it remains unclear how zinc causes the sequential activation of microglia. Here, we examined whether transporter\u2010mediated zinc uptake is necessary for microglial activation. Administration of zinc to microglia activated them through reactive oxygen species (ROS) generation and poly(ADP\u2010ribose) (PAR) formation, which were suppressed by intracellular zinc chelation with 25 \u03bcM TPEN (\n                    <jats:italic>N<\/jats:italic>\n                    ,\n                    <jats:italic>N<\/jats:italic>\n                    ,\n                    <jats:italic>N<\/jats:italic>\n                    \u2032,\n                    <jats:italic>N<\/jats:italic>\n                    \u2032\u2010tetrakis(2\u2010pyridylmethyl)ethylenediamine) or 2 \u03bcM BAPTA\u2010AM (1,2\u2010bis(2\u2010aminophenoxy)ethane\u2010\n                    <jats:italic>N<\/jats:italic>\n                    ,\n                    <jats:italic>N<\/jats:italic>\n                    ,\n                    <jats:italic>N<\/jats:italic>\n                    \u2032,\n                    <jats:italic>N<\/jats:italic>\n                    \u2032\u2010tetraacetic acid\u2010acetoxymethyl ester). The\n                    <jats:sup>65<\/jats:sup>\n                    Zn uptake by microglia was temperature\u2010 and dose\u2010dependent, and it was blocked by metal cations, but not by L\u2010type calcium channel blockers nifedipine and nimodipine. Expression of Zrt\u2010Irt\u2010like protein (ZIP)1, a plasma membrane\u2010type zinc transporter, was detected in microglia, and nickel, a relatively sensitive substrate\/inhibitor of ZIP1, showed\n                    <jats:italic>cis<\/jats:italic>\n                    \u2010 and\n                    <jats:italic>trans<\/jats:italic>\n                    \u2010inhibitory effects on the\n                    <jats:sup>65<\/jats:sup>\n                    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\u2010oxidized ATP, a selective P2\u00d77 receptor antagonist, attenuated the zinc\u2010induced microglial activation via NADPH oxidase and PARP\u20101. Exogenous ATP and 2\u2032(3\u2032)\u2010\n                    <jats:italic>O<\/jats:italic>\n                    \u2010(4\u2010benzoyl\u2010benzoyl) ATP also caused microglial activation through ROS generation and PAR formation. These findings demonstrate that ZIP1\u2010mediated uptake of zinc induces ATP release and autocrine\/paracrine activation of P2X(7) receptors, and then activates microglia, suggesting that zinc transporter\u2010mediated uptake of zinc is a trigger for microglial activation via the NADPH oxidase and PARP\u20101 pathway. \u00a9 2011 Wiley\u2010Liss, Inc.\n                  <\/jats:p>","DOI":"10.1002\/glia.21235","type":"journal-article","created":{"date-parts":[[2011,8,31]],"date-time":"2011-08-31T20:25:11Z","timestamp":1314822311000},"page":"1933-1945","source":"Crossref","is-referenced-by-count":62,"title":["Microglial zinc uptake via zinc transporters induces ATP release and the activation of microglia"],"prefix":"10.1002","volume":"59","author":[{"given":"Youichirou","family":"Higashi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shohei","family":"Segawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takaaki","family":"Matsuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shogo","family":"Nakamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukiko","family":"Kikkawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kentaro","family":"Nishida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuki","family":"Nagasawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2011,8,24]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2000.0751878.x"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2006.03.003"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(87)91355-2"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2011.01303.x"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.6.2473"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/308734a0"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.22.15493"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M901255200"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(97)00559-3"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2004.02947.x"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1132559"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00143.2001"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00271.2007"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-291X(89)80042-7"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00509203"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/jlb.60.6.677"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20030975"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.17-20-07673.1997"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.6250-09.2010"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.20606"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.185.3.579"},{"key":"e_1_2_5_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2008.05599.x"},{"key":"e_1_2_5_24_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M101772200"},{"key":"e_1_2_5_25_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M412188200"},{"key":"e_1_2_5_26_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.2000.279.2.H692"},{"key":"e_1_2_5_27_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.21-06-01975.2001"},{"key":"e_1_2_5_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/308736a0"},{"key":"e_1_2_5_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/0304-4165(95)00082-M"},{"key":"e_1_2_5_30_1","doi-asserted-by":"publisher","DOI":"10.1054\/ceca.1999.0092"},{"key":"e_1_2_5_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2005.04.003"},{"key":"e_1_2_5_32_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.58.1.82"},{"key":"e_1_2_5_33_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00549.2007"},{"key":"e_1_2_5_34_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-003-3148-y"},{"key":"e_1_2_5_35_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.174.4.2288"},{"key":"e_1_2_5_36_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0508606103"},{"key":"e_1_2_5_37_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1236-08.2008"},{"key":"e_1_2_5_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/emm.2007.89"},{"key":"e_1_2_5_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.20592"},{"key":"e_1_2_5_40_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.272.5264.1013"},{"key":"e_1_2_5_41_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.2005.03926.x"},{"key":"e_1_2_5_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0707361"},{"key":"e_1_2_5_43_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.105.021436"},{"key":"e_1_2_5_44_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11302-007-9077-8"},{"key":"e_1_2_5_45_1","doi-asserted-by":"publisher","DOI":"10.1097\/00004647-199609000-00017"},{"key":"e_1_2_5_46_1","doi-asserted-by":"publisher","DOI":"10.1089\/neu.2005.22.88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