{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T21:27:13Z","timestamp":1790630833814,"version":"4.1.0"},"reference-count":59,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2019,9,18]],"date-time":"2019-09-18T00:00:00Z","timestamp":1568764800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Acta Physiologica"],"published-print":{"date-parts":[[2020,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>The mode of action by which doxapram acts as a respiratory stimulant in humans is controversial. Studies in rodent models, have shown that doxapram is a more potent and selective inhibitor of TASK\u20101 and TASK\u20101\/TASK\u20103 heterodimer channels, than TASK\u20103. Here we investigate the direct effect of doxapram and chirally separated, individual positive and negative enantiomers of the compound, on both human and mouse, homodimeric and heterodimeric variants of TASK\u20101 and TASK\u20103.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Whole\u2010cell patch clamp electrophysiology on tsA201 cells was used to assess the potency of doxapram on cloned human or mouse TASK\u20101, TASK\u20103 and TASK\u20102 channels. Mutations of amino acids in the pore\u2010lining region of TASK\u20103 channels were introduced using site\u2010directed mutagenesis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Doxapram was an equipotent inhibitor of human TASK\u20101 and TASK\u20103 channels, compared with mouse channel variants, where it was more selective for TASK\u20101 and heterodimers of TASK\u20101 and TASK\u20103. The effect of doxapram could be attenuated by either the removal of the C\u2010terminus of human TASK\u20103 channels or mutations of particular hydrophobic residues in the pore\u2010lining region. These mutations, however, did not alter the effect of a known extracellular inhibitor of TASK\u20103, zinc. The positive enantiomer of doxapram, GAL\u2010054, was a more potent antagonist of TASK channels, than doxapram, whereas the negative enantiomer, GAL\u2010053, had little inhibitory effect.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These data show that in contrast to rodent channels, doxapram is a potent inhibitor of both TASK\u20101 and TASK\u20103 human channels, providing further understanding of the pharmacological profile of doxapram in humans and informing the development of new therapeutic agents.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/apha.13361","type":"journal-article","created":{"date-parts":[[2019,8,19]],"date-time":"2019-08-19T03:44:44Z","timestamp":1566186284000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Effects of the ventilatory stimulant, doxapram on human TASK\u20103 (KCNK9, K2P9.1) channels and TASK\u20101 (KCNK3, K2P3.1) channels"],"prefix":"10.1111","volume":"228","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6772-0107","authenticated-orcid":false,"given":"Kevin P.","family":"Cunningham","sequence":"first","affiliation":[{"name":"Medway School of Pharmacy University of Greenwich and University of Kent Chatham Maritime UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. Euan","family":"MacIntyre","sequence":"additional","affiliation":[{"name":"Department of Drug Discovery Galleon Pharmaceuticals, Inc Horsham Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6094-2890","authenticated-orcid":false,"given":"Alistair","family":"Mathie","sequence":"additional","affiliation":[{"name":"Medway School of Pharmacy University of Greenwich and University of Kent Chatham Maritime UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6778-9929","authenticated-orcid":false,"given":"Emma L.","family":"Veale","sequence":"additional","affiliation":[{"name":"Medway School of Pharmacy University of Greenwich and University of Kent Chatham Maritime UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,9,18]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm00333a012"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2008.05.010"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-6576.1966.tb00993.x"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1982.52.5.1261"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.14814\/phy2.13876"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.2456613"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3940(90)90846-2"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(90)91470-2"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1997.sp021890"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.2000.00135.x"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.resp.2007.02.013"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(02)03181-5"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2009.171181"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2013.262022"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1213\/01.ane.0000194289.34345.63"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-015-1689-1"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.200910302"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1810-08.2008"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1042\/cs0650065"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.227884"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-014-1665-1"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.115.100107"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2008.07.010"},{"issue":"1","key":"e_1_2_7_25_1","article-title":"Enantiomeric separation of doxapram reveals a superior respiratory stimulant, GAL\u2010054","volume":"26","author":"Golder FJ","year":"2012","journal-title":"FASEB Journal"},{"issue":"1","key":"e_1_2_7_26_1","article-title":"GAL\u2010021 acts as a novel respiratory stimulant in non\u2010human primates","volume":"26","author":"Golder FJ","year":"2012","journal-title":"FASEB Journal"},{"issue":"1","key":"e_1_2_7_27_1","article-title":"Reversal of opioid\u2010induced respiratory depression by the (+)\u2010 enantiomer, GAL\u2010054, but not the (\u2010)\u2010 enantiomer, GAL\u2010053, of doxapram","volume":"26","author":"Golder FJ","year":"2012","journal-title":"FASEB J"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.resp.2013.06.010"},{"key":"e_1_2_7_29_1","unstructured":"CunninghamKP MacIntyreDE MathieA VealeEL.The ventilatory stimulant doxapram is an equally potent inhibitor of the human two\u2010pore domain potassium (K2P) channels TASK\u20103 (KCNK9) and TASK\u20101 (KCNK3). 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