{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T12:47:32Z","timestamp":1790254052748,"version":"4.1.0"},"reference-count":97,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2006,3,17]],"date-time":"2006-03-17T00:00:00Z","timestamp":1142553600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J of Neuroscience Research"],"published-print":{"date-parts":[[2006,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Microglia, the resident macrophages of the CNS, are responsible for the innate immune response in the brain and participate in the pathogenesis of certain neurodegenerative disorders. Chemokines initiate activation and migration of microglia. The \u03b2\u2010chemokine CCL5 induces an elevation in intracellular calcium concentration ([Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>) in human microglia. Here, we examined the signal transduction pathway linking activation of chemokine receptor CCR5 to an elevation in [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> in cultured microglia by using pharmacological approaches in combination with Fura\u20102\u2010based digital imaging. The CCL5\u2010induced response required Janus kinase (Jak) activity and the stimulation of an inhibitory G protein. Multiple downstream signaling pathways were involved, including phosphatidylinositol 3\u2010kinase (PI3K), Bruton's tyrosine kinase (Btk), and phospholipase C (PLC)\u2010mediated release of Ca<jats:sup>2+<\/jats:sup> from inositol 1,4,5\u2010trisphosphate (IP<jats:sub>3<\/jats:sub>)\u2010sensitive stores. Activation of both the kinase and the lipase pathways was required for eliciting the Ca<jats:sup>2+<\/jats:sup> response. However, the majority of the [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> increase was derived from sources activated by NAD metabolites. Cyclic ADP\u2010ribose (cADPR) evoked Ca<jats:sup>2+<\/jats:sup> release from intracellular stores, and ADPR evoked Ca<jats:sup>2+<\/jats:sup> influx via a nimodipine\u2010sensitive channel. Thus, a multistep cascade couples CCR5 activation to Ca<jats:sup>2+<\/jats:sup> increases in human microglia. Because changes in [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> affect chemotaxis, secretion, and gene expression, pharmacologic modulation of this pathway may alter inflammatory and degenerative processes in the CNS. \u00a9 2006 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/jnr.20839","type":"journal-article","created":{"date-parts":[[2006,3,17]],"date-time":"2006-03-17T23:17:07Z","timestamp":1142637427000},"page":"1471-1484","source":"Crossref","is-referenced-by-count":38,"title":["CCL5 evokes calcium signals in microglia through a kinase\u2010, phosphoinositide\u2010, and nucleotide\u2010dependent mechanism"],"prefix":"10.1002","volume":"83","author":[{"given":"C.R.","family":"Shideman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P.K.","family":"Peterson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.A.","family":"Thayer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2006,3,17]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2567.1998.00603.x"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/00126334-200210012-00004"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.7569902"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1150"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M204891200"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1515\/BC.2001.050"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M108232200"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.30.17739"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1994.266.6.C1650"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(02)00699-2"},{"key":"e_1_2_6_12_1","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1196\/annals.1322.021","article-title":"Autocrine and paracrine calcium signaling by the CD38\/NAD+\/cyclic ADP\u2010ribose system","volume":"1028","author":"De Flora A","year":"2004","journal-title":"Ann N Y Acad Sci"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/381661a0"},{"key":"e_1_2_6_14_1","doi-asserted-by":"crossref","first-page":"1944","DOI":"10.4049\/jimmunol.160.4.1944","article-title":"Cytokine regulation of human microglial cell IL\u20108 production","volume":"160","author":"Ehrlich LC","year":"1998","journal-title":"J Immunol"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-5728(03)00009-2"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.77.4.2539-2549.2003"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.283.5400.393"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80384-0"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1521-1878(199901)21:1<17::AID-BIES3>3.0.CO;2-4"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00232-001-0080-7"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.170.10.5235"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)83641-4"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/18024"},{"key":"e_1_2_6_24_1","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1042\/bj3450207","article-title":"cADP\u2010ribose potentiates cytosolic Ca2+ elevation and Ca2+ entry via L\u2010type voltage\u2010activated Ca2+ channels in NG108\u201015 neuronal cells","volume":"345","author":"Hashii M","year":"2000","journal-title":"Biochem J"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-4522(00)00101-9"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/16711"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/jlb.65.6.815"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1177\/026988110001400307"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M311985200"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1999.1234"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M304487200"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(94)90927-X"},{"key":"e_1_2_6_33_1","doi-asserted-by":"crossref","first-page":"1920","DOI":"10.1523\/JNEUROSCI.14-04-01920.1994","article-title":"Opioids mobilize calcium from inositol 1,4,5\u2010trisphosphate\u2010sensitive stores in NG108\u201015 cells","volume":"14","author":"Jin WZ","year":"1994","journal-title":"J Neurosci"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M009374200"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1385\/IR:23:2-3:147"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.24.22.9986-9999.2004"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1042\/0264-6021:3600017"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2005.02.033"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00331.2003"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M407263200"},{"key":"e_1_2_6_41_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4419-8632-0_53"},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.287.5455.1046"},{"key":"e_1_2_6_43_1","doi-asserted-by":"publisher","DOI":"10.1006\/clin.1998.4518"},{"key":"e_1_2_6_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0091-6749(03)80114-8"},{"key":"e_1_2_6_45_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110390200"},{"key":"e_1_2_6_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(91)81108-K"},{"key":"e_1_2_6_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1357-2725(00)00035-2"},{"key":"e_1_2_6_48_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.14.9587"},{"key":"e_1_2_6_49_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.164.12.6538"},{"key":"e_1_2_6_50_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.19.1.397"},{"key":"e_1_2_6_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/379645a0"},{"key":"e_1_2_6_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-510X(02)00207-1"},{"key":"e_1_2_6_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2004.10.001"},{"key":"e_1_2_6_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2004.04.100"},{"key":"e_1_2_6_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2004.04.007"},{"key":"e_1_2_6_56_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00057.2003"},{"key":"e_1_2_6_57_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm1101-1209"},{"key":"e_1_2_6_58_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.172.3.1896"},{"key":"e_1_2_6_59_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/19.12.2793"},{"key":"e_1_2_6_60_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.47.2.509-517.2003"},{"key":"e_1_2_6_61_1","doi-asserted-by":"publisher","DOI":"10.1038\/35079100"},{"key":"e_1_2_6_62_1","first-page":"31","volume-title":"In defense of the brain: current concepts in the immunopathogenesis and clinical aspects of CNS infections","author":"Peterson PK","year":"1997"},{"key":"e_1_2_6_63_1","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/175.2.478"},{"key":"e_1_2_6_64_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.13.7205"},{"key":"e_1_2_6_65_1","doi-asserted-by":"publisher","DOI":"10.1002\/bies.20157"},{"key":"e_1_2_6_66_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1203958"},{"key":"e_1_2_6_67_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M409592200"},{"key":"e_1_2_6_68_1","doi-asserted-by":"publisher","DOI":"10.1006\/clim.1999.4732"},{"key":"e_1_2_6_69_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M211745200"},{"key":"e_1_2_6_70_1","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.17.4.942-964.2004"},{"key":"e_1_2_6_71_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.13.7297"},{"key":"e_1_2_6_72_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1062473"},{"key":"e_1_2_6_73_1","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/7.2.163"},{"key":"e_1_2_6_74_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.0953-816x.2001.01661.x"},{"key":"e_1_2_6_75_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1521-4141(199903)29:03<897::AID-IMMU897>3.0.CO;2-5"},{"key":"e_1_2_6_76_1","doi-asserted-by":"publisher","DOI":"10.2174\/1389450043345209"},{"key":"e_1_2_6_77_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri1226"},{"key":"e_1_2_6_78_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2567.2004.01863.x"},{"key":"e_1_2_6_79_1","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0403128"},{"key":"e_1_2_6_80_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200323897"},{"key":"e_1_2_6_81_1","doi-asserted-by":"publisher","DOI":"10.1034\/j.1600-065X.2000.17712.x"},{"key":"e_1_2_6_82_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni890"},{"key":"e_1_2_6_83_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00583753"},{"key":"e_1_2_6_84_1","first-page":"PE34","article-title":"Is dimerization of chemokine receptors functionally relevant?","author":"Thelen M","year":"2001","journal-title":"Sci STKE"},{"key":"e_1_2_6_85_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(01)00557-8"},{"key":"e_1_2_6_86_1","doi-asserted-by":"publisher","DOI":"10.1515\/BC.2004.045"},{"key":"e_1_2_6_87_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.70.1.535"},{"key":"e_1_2_6_88_1","doi-asserted-by":"publisher","DOI":"10.2741\/A172"},{"key":"e_1_2_6_89_1","doi-asserted-by":"publisher","DOI":"10.1096\/fasebj.13.13.1699"},{"key":"e_1_2_6_90_1","doi-asserted-by":"publisher","DOI":"10.1016\/0167-4889(93)90199-Y"},{"key":"e_1_2_6_91_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)00005-4"},{"key":"e_1_2_6_92_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature01807"},{"key":"e_1_2_6_93_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.2200125"},{"key":"e_1_2_6_94_1","doi-asserted-by":"publisher","DOI":"10.1038\/40173"},{"key":"e_1_2_6_95_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0065-3527(08)60305-X"},{"key":"e_1_2_6_96_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1044-5323(02)00123-9"},{"key":"e_1_2_6_97_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M010750200"},{"key":"e_1_2_6_98_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-4644(19981001)71:1<36::AID-JCB4>3.0.CO;2-2"}],"container-title":["Journal of Neuroscience Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fjnr.20839","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jnr.20839","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,9]],"date-time":"2023-10-09T15:35:28Z","timestamp":1696865728000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jnr.20839"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2006,3,17]]},"references-count":97,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2006,6]]}},"alternative-id":["10.1002\/jnr.20839"],"URL":"https:\/\/doi.org\/10.1002\/jnr.20839","archive":["Portico"],"relation":{},"ISSN":["0360-4012","1097-4547"],"issn-type":[{"value":"0360-4012","type":"print"},{"value":"1097-4547","type":"electronic"}],"subject":[],"published":{"date-parts":[[2006,3,17]]}}}