{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T22:32:45Z","timestamp":1778884365941,"version":"3.51.4"},"reference-count":65,"publisher":"Wiley","issue":"15","license":[{"start":{"date-parts":[[2019,6,17]],"date-time":"2019-06-17T00:00:00Z","timestamp":1560729600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["LE 3600\/1\u20101"],"award-info":[{"award-number":["LE 3600\/1\u20101"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2019,8]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>The ether\u2010\u00e0\u2010go\u2010go (Eag) K<jats:sub>v<\/jats:sub> superfamily comprises closely related K<jats:sub>v<\/jats:sub>10, K<jats:sub>v<\/jats:sub>11, and K<jats:sub>v<\/jats:sub>12 subunits. K<jats:sub>v<\/jats:sub>11.1 (termed hERG in humans) gained much attention, as drug\u2010induced inhibition of these channels is a frequent cause of sudden death in humans. The exclusive drug sensitivity of K<jats:sub>v<\/jats:sub>11.1 can be explained by central drug\u2010binding pockets that are absent in most other channels. Currently, it is unknown whether K<jats:sub>v<\/jats:sub>12 channels are equipped with an analogous drug\u2010binding pocket and whether drug\u2010binding properties are conserved in all Eag superfamily members.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>We analysed sensitivity of recombinant K<jats:sub>v<\/jats:sub>12.1 channels to quinine, a substituted quinoline that blocks K<jats:sub>v<\/jats:sub>10.1 and K<jats:sub>v<\/jats:sub>11.1 at low micromolar concentrations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Quinine inhibited K<jats:sub>v<\/jats:sub>12.1, but its affinity was 10\u2010fold lower than for K<jats:sub>v<\/jats:sub>11.1. Contrary to K<jats:sub>v<\/jats:sub>11.1, quinine inhibited K<jats:sub>v<\/jats:sub>12.1 in a largely voltage\u2010independent manner and induced channel opening at more depolarised potentials. Low sensitivity of K<jats:sub>v<\/jats:sub>12.1 and characteristics of quinine\u2010dependent inhibition were determined by histidine 462, as site\u2010directed mutagenesis of this residue into the homologous tyrosine of K<jats:sub>v<\/jats:sub>11.1 conferred K<jats:sub>v<\/jats:sub>11.1\u2010like quinine block to K<jats:sub>v<\/jats:sub>12.1(H462Y). Molecular modelling demonstrated that the low affinity of K<jats:sub>v<\/jats:sub>12.1 was determined by only weak interactions of residues in the central cavity with quinine. In contrast, more favourable interactions can explain the higher quinine sensitivity of K<jats:sub>v<\/jats:sub>12.1(H462Y) and K<jats:sub>v<\/jats:sub>11.1 channels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>The quinoline\u2010binding \u201cmotif\u201d is not conserved within the Eag superfamily, although the overall architecture of these channels is apparently similar. Our findings highlight functional and pharmacological diversity in this group of evolutionary\u2010conserved channels.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.14693","type":"journal-article","created":{"date-parts":[[2019,4,29]],"date-time":"2019-04-29T11:49:43Z","timestamp":1556538583000},"page":"2708-2723","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Histidine at position 462 determines the low quinine sensitivity of ether\u2010\u00e0\u2010go\u2010go channel superfamily member K<sub>v<\/sub>12.1"],"prefix":"10.1111","volume":"176","author":[{"given":"Marlen","family":"Dierich","sequence":"first","affiliation":[{"name":"Department of Neurophysiology, Institute of Physiology and Pathophysiology Philipps\u2010University Marburg  Marburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Willem B.","family":"van Ham","sequence":"additional","affiliation":[{"name":"Department of Medical Physiology University Medical Center Utrecht  Utrecht The Netherlands"},{"name":"Department of Pharmacology and Toxicology University of Vienna  Vienna Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Stary\u2010Weinzinger","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology University of Vienna  Vienna Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3259-6481","authenticated-orcid":false,"given":"Michael G.","family":"Leitner","sequence":"additional","affiliation":[{"name":"Department of Neurophysiology, Institute of Physiology and Pathophysiology Philipps\u2010University Marburg  Marburg Germany"},{"name":"Division of Physiology, Department of Physiology and Medical Physics Medical University of Innsbruck  Innsbruck Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2019,6,17]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"crossref","unstructured":"Abraham M. 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