{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T09:54:27Z","timestamp":1790416467920,"version":"4.1.0"},"reference-count":44,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2017,9,22]]},"abstract":"\n Background<\/jats:title>\n \n Heterozygous loss of function mutations in the\n \n KCNK<\/jats:styled-content>\n 3\n <\/jats:italic>\n gene cause hereditary pulmonary arterial hypertension (\n PAH<\/jats:styled-content>\n ).\n \n KCNK<\/jats:styled-content>\n 3\n <\/jats:italic>\n encodes an acid\u2010sensitive potassium channel, which contributes to the resting potential of human pulmonary artery smooth muscle cells.\n KCNK<\/jats:styled-content>\n 3 is widely expressed in the body, and dimerizes with other\n KCNK<\/jats:styled-content>\n 3 subunits, or the closely related, acid\u2010sensitive\n KCNK<\/jats:styled-content>\n 9 channel.\n <\/jats:p>\n <\/jats:sec>\n \n Methods and Results<\/jats:title>\n \n We engineered homomeric and heterodimeric mutant and nonmutant\n KCNK<\/jats:styled-content>\n 3 channels associated with\n PAH<\/jats:styled-content>\n . Using whole\u2010cell patch\u2010clamp electrophysiology in human pulmonary artery smooth muscle and\n COS<\/jats:styled-content>\n 7 cell lines, we determined that homomeric and heterodimeric mutant channels in heterozygous\n KCNK<\/jats:styled-content>\n 3 conditions lead to mutation\u2010specific severity of channel dysfunction. Both wildtype and mutant\n KCNK<\/jats:styled-content>\n 3 channels were activated by\n ONO<\/jats:styled-content>\n \u2010\n RS<\/jats:styled-content>\n \u2010082 (10\u00a0\u03bcmol\/L), causing cell hyperpolarization. We observed robust gene expression of\n \n KCNK<\/jats:styled-content>\n 3\n <\/jats:italic>\n in healthy and familial\n PAH<\/jats:styled-content>\n patient lungs, but no quantifiable expression of\n \n KCNK<\/jats:styled-content>\n 9\n <\/jats:italic>\n , and demonstrated in functional studies that\n KCNK<\/jats:styled-content>\n 9 minimizes the impact of select\n KCNK<\/jats:styled-content>\n 3 mutations when the 2 channel subunits co\u2010assemble.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n Heterozygous\n \n KCNK<\/jats:styled-content>\n 3\n <\/jats:italic>\n mutations in\n PAH<\/jats:styled-content>\n lead to variable loss of channel function via distinct mechanisms. Homomeric and heterodimeric mutant\n KCNK<\/jats:styled-content>\n 3 channels represent novel therapeutic substrates in\n PAH<\/jats:styled-content>\n . Pharmacological and\n pH<\/jats:styled-content>\n \u2010dependent activation of wildtype and mutant\n KCNK<\/jats:styled-content>\n 3 channels in pulmonary artery smooth muscle cells leads to membrane hyperpolarization. Co\u2010assembly of\n KCNK<\/jats:styled-content>\n 3 with\n KCNK<\/jats:styled-content>\n 9 subunits may provide protection against\n KCNK<\/jats:styled-content>\n 3 loss of function in tissues where both\n \n KCNK<\/jats:styled-content>\n 9\n <\/jats:italic>\n and\n \n KCNK<\/jats:styled-content>\n 3\n <\/jats:italic>\n are expressed, contributing to the lung\u2010specific phenotype observed clinically in patients with\n PAH<\/jats:styled-content>\n because of\n \n KCNK<\/jats:styled-content>\n 3\n <\/jats:italic>\n mutations.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/jaha.117.006465","type":"journal-article","created":{"date-parts":[[2017,9,9]],"date-time":"2017-09-09T20:10:17Z","timestamp":1504987817000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":43,"title":["The Impact of Heterozygous\n KCNK3<\/i>\n Mutations Associated With Pulmonary Arterial Hypertension on Channel Function and Pharmacological Recovery"],"prefix":"10.1161","volume":"6","author":[{"given":"Michael S.","family":"Bohnen","sequence":"first","affiliation":[{"name":"Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danilo","family":"Roman\u2010Campos","sequence":"additional","affiliation":[{"name":"New York Stem Cell Foundation Research Institute, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecile","family":"Terrenoire","sequence":"additional","affiliation":[{"name":"Department of Biophysics, Paulista School of Medicine, Federal University of Sao Paulo, Sao Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack","family":"Jnani","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin J.","family":"Sampson","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy K.","family":"Chung","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert S.","family":"Kass","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehv317"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/path.4833"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1211097"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/16.17.5464"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000219677.12988.e9"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00029.2009"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000099883.68414.61"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.115.020951"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0705691"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C100184200"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M107138200"},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1408-04.2004"},{"key":"e_1_3_5_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2015.01.017"},{"key":"e_1_3_5_15_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2003.054387"},{"key":"e_1_3_5_16_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2009.171181"},{"key":"e_1_3_5_17_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M000030200"},{"key":"e_1_3_5_18_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.13.9340"},{"key":"e_1_3_5_19_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201309-1697OC"},{"key":"e_1_3_5_20_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00050.2004"},{"key":"e_1_3_5_21_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00405.2006"},{"key":"e_1_3_5_22_2","unstructured":"Zou B Flaherty DP Simpson DS Maki BE Miller MR Shi J Wu M McManus OB Golden JE Aube J Li M. 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