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We transfected HEK293 cells or injected<jats:italic>Xenopus laevis<\/jats:italic>oocytes with the cDNA coding for rat P2X<jats:sub>4<\/jats:sub>receptor. Application of 0.1\u201310\u2003\u03bcM alfaxolone potentiated within 60\u2010s the 1\u2003\u03bcM ATP\u2010evoked currents with a maximal potentiation of 1.8 and 2.6\u2010fold in HEK293 or oocytes cells respectively. Allopregnalolone or 3\u03b1, 21\u2010dihydroxy\u20105\u03b1\u2010pregnan\u201020\u2010one (THDOC) also potentiated the ATP\u2010gated currents but with a maximal effect only averaging 1.25 and 1.35\u2010fold respectively. In contrast, 0.3\u201310\u2003\u03bcM pregnanolone, but not its sulfated derivative, inhibited the ATP\u2010gated currents; the maximal inhibition reached 40% in both cell types. THDOC, but not other neurosteroids increased significantly the \u03c4<jats:sub>off<\/jats:sub>of the ATP\u2010evoked currents, revealing another mode of neurosteroid modulation. Sexual steroids such as 17\u03b2\u2010estradiol or progesterone were inactive revealing explicit structural requirements. Alfaxolone or THDOC at concentrations 30\u2010 to 100\u2010fold larger than required to modulate the receptor, gated the P2X<jats:sub>4<\/jats:sub>receptor eliciting ATP\u2010like currents that were reduced with suramin or brilliant blue G, but potentiated the P2X<jats:sub>4<\/jats:sub>receptor more than 10\u2010fold by 10\u2003\u03bcM zinc. In conclusion, neurosteroids rapidly modulate via non\u2010genomic mechanisms and with nanomolar potencies, the P2X4 receptor interacting likely at distinct modulator sites.<\/jats:p>","DOI":"10.1111\/j.1471-4159.2009.06166.x","type":"journal-article","created":{"date-parts":[[2009,5,13]],"date-time":"2009-05-13T10:24:21Z","timestamp":1242210261000},"page":"734-744","source":"Crossref","is-referenced-by-count":19,"title":["Neurosteroids differentially modulate P2X<sub>4<\/sub>ATP\u2010gated channels through non\u2010genomic interactions"],"prefix":"10.1111","volume":"110","author":[{"given":"Juan Francisco","family":"Codocedo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felipe E.","family":"Rodr\u00edguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Pablo","family":"Huidobro\u2010Toro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2009,6,25]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2000.0741529.x"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2006.04343.x"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1159\/000156489"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M412265200"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2005.07.021"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000257836.09570.e1"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-007-6497-0"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00043.2006"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd746"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M305177200"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M706925200"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1006\/frne.1999.0188"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2003.046078"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(84)90299-3"},{"key":"e_1_2_7_16_1","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/S0022-5347(25)00332-5","article-title":"Structure\u2010activity relationships for steroid interaction with the gamma\u2010aminobutyric acidA receptor complex","volume":"241","author":"Harrison N. 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