{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T05:50:32Z","timestamp":1780638632888,"version":"3.54.1"},"reference-count":33,"publisher":"Wiley","issue":"17","license":[{"start":{"date-parts":[[2023,4,25]],"date-time":"2023-04-25T00:00:00Z","timestamp":1682380800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2023,9]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>Itch is associated with several pathologies and is a common drug\u2010induced side effect. Chloroquine (CQ) is reported to induce itch by activating the Mas\u2010related G protein\u2010coupled receptor MrgprA3 and subsequently TRPA1. In this study, we demonstrate that CQ employs at least two MrgprA3\u2010independent mechanisms to activate or sensitize TRPA1 and TRPV1.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Patch clamp and calcium imaging were utilized to examine effects of CQ on TRPA1 and TRPV1 expressed in HEK 293T cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>In calcium imaging, CQ induces a concentration\u2010dependent but MrgprA3\u2010independent activation of TRPA1 and TRPV1. Although CQ itself inhibits TRPA1 and TRPV1 in patch clamp recordings, co\u2010application of CQ and ultraviolet A (UVA) light evokes membrane currents through both channels. This effect is inhibited by the reducing agent dithiothreitol (DTT) and is reduced on mutants lacking cysteine residues accounting for reactive oxygen species (ROS) sensitivity. The combination of CQ and UVA light triggers an accumulation of intracellular ROS, removes fast inactivation of voltage\u2010gated sodium currents and activates TRPV2. On the other hand, CQ is a weak base and induces intracellular alkalosis. Intracellular alkalosis can activate TRPA1 and TRPV1, and CQ applied at alkaline pH values indeed activates both channels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Our data reveal novel pharmacological properties of CQ, allowing activation of TRPA1 and TRPV1 via photosensitization as well as intracellular alkalosis. These findings add more complexity to the commonly accepted dogma that CQ\u2010induced itch is specifically mediated by MrgprA3 coupling to TRPA1.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.16072","type":"journal-article","created":{"date-parts":[[2023,3,17]],"date-time":"2023-03-17T03:28:46Z","timestamp":1679023726000},"page":"2214-2229","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Molecular mechanisms of MrgprA3\u2010independent activation of the transient receptor potential ion channels TRPA1 and TRPV1 by chloroquine"],"prefix":"10.1111","volume":"180","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-0958-1895","authenticated-orcid":false,"given":"Tabea C.","family":"Fricke","sequence":"first","affiliation":[{"name":"Department of Anesthesiology and Intensive Care Medicine Hannover Medical School  Hanover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Pantke","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care Medicine Hannover Medical School  Hanover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bjarne","family":"L\u00fcttmann","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care Medicine Hannover Medical School  Hanover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank G.","family":"Echtermeyer","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care Medicine Hannover Medical School  Hanover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Herzog","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care Medicine Hannover Medical School  Hanover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirjam J.","family":"Eberhardt","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care Medicine Hannover Medical School  Hanover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1121-6387","authenticated-orcid":false,"given":"Andreas","family":"Leffler","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care Medicine Hannover Medical School  Hanover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,4,25]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15538"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15539"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4268-15.2016"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2230.2008.02704.x"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.131712"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15868"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4901-08.2009"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2005.07.005"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0749.1999.tb00504.x"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1904332116"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI35957"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1080\/10915810290169909"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0033-21.2021"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3289"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-008-0477-6"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.alit.2016.10.003"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2014.02.007"},{"key":"e_1_2_13_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15178"},{"key":"e_1_2_13_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-662-44605-8_5"},{"key":"e_1_2_13_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.11.034"},{"key":"e_1_2_13_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12264-012-1207-9"},{"key":"e_1_2_13_23_1","first-page":"27","article-title":"Chloroquine\u2010induced pruritus: Its impact on chloroquine utilization in malaria control in Dar es Salaam","volume":"94","author":"Mnyika K. 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