{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T16:55:10Z","timestamp":1789750510623,"version":"4.0.1"},"reference-count":112,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,9,22]],"date-time":"2022-09-22T00:00:00Z","timestamp":1663804800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Pulmonary arterial hypertension (PAH) is a devastating disease with high morbidity and mortality. Deleterious remodeling in the pulmonary arterial system leads to irreversible arterial constriction and elevated pulmonary arterial pressures, right heart failure, and eventually death. The difficulty in treating PAH stems in part from the complex nature of disease pathogenesis, with several signaling compounds known to be involved (e.g., endothelin-1, prostacyclins) which are indeed targets of PAH therapy. Over the last decade, potassium channelopathies were established as novel causes of PAH. More specifically, loss-of-function mutations in the KCNK3 gene that encodes the two-pore-domain potassium channel KCNK3 (or TASK-1) and loss-of-function mutations in the ABCC8 gene that encodes a key subunit, SUR1, of the ATP-sensitive potassium channel (KATP) were established as the first two potassium channelopathies in human cohorts with pulmonary arterial hypertension. Moreover, voltage-gated potassium channels (Kv) represent a third family of potassium channels with genetic changes observed in association with PAH. While other ion channel genes have since been reported in association with PAH, this review focuses on KCNK3, KATP, and Kv potassium channels as promising therapeutic targets in PAH, with recent experimental pharmacologic discoveries significantly advancing the field.<\/jats:p>","DOI":"10.3390\/biom12101341","type":"journal-article","created":{"date-parts":[[2022,9,22]],"date-time":"2022-09-22T05:33:14Z","timestamp":1663824794000},"page":"1341","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Potassium Channels as Therapeutic Targets in Pulmonary Arterial Hypertension"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0908-7889","authenticated-orcid":false,"given":"Gabriel","family":"Redel-Traub","sequence":"first","affiliation":[{"name":"Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin J.","family":"Sampson","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Therapeutics, Columbia University Irving Medical Center, New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert S.","family":"Kass","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Therapeutics, Columbia University Irving Medical Center, New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7010-6888","authenticated-orcid":false,"given":"Michael S.","family":"Bohnen","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1801913","DOI":"10.1183\/13993003.01913-2018","article-title":"Haemodynamic definitions and updated clinical classification of pulmonary hypertension","volume":"53","author":"Simonneau","year":"2019","journal-title":"Eur. Respir. J."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Humbert, M., Kovacs, G., Hoeper, M.M., Badagliacca, R., Berger, R.M.F., Brida, M., Carlsen, J., Coats, A.J.S., Escribano-Subias, P., and Ferrari, P. (2022). 2022 ESC\/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur. Respir. J., 2200879.","DOI":"10.1183\/13993003.00879-2022"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1183\/13993003.00798-2015","article-title":"Potassium channels in pulmonary arterial hypertension","volume":"46","author":"Boucherat","year":"2015","journal-title":"Eur. Respir. J."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Le Ribeuz, H., Capuano, V., Girerd, B., Humbert, M., Montani, D., and Antigny, F. (2020). Implication of Potassium Channels in the Pathophysiology of Pulmonary Arterial Hypertension. Biomolecules, 10.","DOI":"10.3390\/biom10091261"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"S10","DOI":"10.1016\/j.jacc.2009.04.006","article-title":"Inflammation, growth factors, and pulmonary vascular remodeling","volume":"54","author":"Hassoun","year":"2009","journal-title":"J. Am.Coll. Cardiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1700745","DOI":"10.1183\/13993003.00745-2017","article-title":"Pulmonary vascular endothelium: The orchestra conductor in respiratory diseases: Highlights from basic research to therapy","volume":"51","author":"Huertas","year":"2018","journal-title":"Eur. Respir. J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2189","DOI":"10.1161\/CIRCULATIONAHA.114.006974","article-title":"Advances in therapeutic interventions for patients with pulmonary arterial hypertension","volume":"130","author":"Humbert","year":"2014","journal-title":"Circulation"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1801887","DOI":"10.1183\/13993003.01887-2018","article-title":"Pathology and pathobiology of pulmonary hypertension: State of the art and research perspectives","volume":"53","author":"Humbert","year":"2019","journal-title":"Eur. Respir. J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"eaba2470","DOI":"10.1126\/sciadv.aba2470","article-title":"DNA methyltransferase 3B deficiency unveils a new pathological mechanism of pulmonary hypertension","volume":"6","author":"Yan","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"L508","DOI":"10.1152\/ajplung.00165.2020","article-title":"Glucose-6-phosphate dehydrogenase deficiency contributes to metabolic abnormality and pulmonary hypertension","volume":"320","author":"Varghese","year":"2021","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1056\/NEJMoa1211097","article-title":"A novel channelopathy in pulmonary arterial hypertension","volume":"369","author":"Ma","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e002087","DOI":"10.1161\/CIRCGEN.118.002087","article-title":"Loss-of-Function ABCC8 Mutations in Pulmonary Arterial Hypertension","volume":"11","author":"Bohnen","year":"2018","journal-title":"Circ. Genom. Precis. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1038\/376690a0","article-title":"A new family of outwardly rectifying potassium channel proteins with two pore domains in tandem","volume":"376","author":"Ketchum","year":"1995","journal-title":"Nature"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1002\/j.1460-2075.1996.tb00437.x","article-title":"TWIK-1, a ubiquitous human weakly inward rectifying K+ channel with a novel structure","volume":"15","author":"Lesage","year":"1996","journal-title":"EMBO J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"24449","DOI":"10.1074\/jbc.C100184200","article-title":"Block of Kcnk3 by protons. Evidence that 2-P-domain potassium channel subunits function as homodimers","volume":"276","author":"Lopes","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1161\/01.RES.0000219677.12988.e9","article-title":"Impact of TASK-1 in human pulmonary artery smooth muscle cells","volume":"98","author":"Olschewski","year":"2006","journal-title":"Circ. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1700754","DOI":"10.1183\/13993003.00754-2017","article-title":"TASK-1 (KCNK3) channels in the lung: From cell biology to clinical implications","volume":"50","author":"Olschewski","year":"2017","journal-title":"Eur. Respir. J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1046\/j.1440-1681.2002.03653.x","article-title":"Potassium channels underlying the resting potential of pulmonary artery smooth muscle cells","volume":"29","author":"Gurney","year":"2002","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1161\/01.RES.0000099883.68414.61","article-title":"Two-pore domain K channel, TASK-1, in pulmonary artery smooth muscle cells","volume":"93","author":"Gurney","year":"2003","journal-title":"Circ. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1038\/sj.bjp.0705691","article-title":"Functional evidence of a role for two-pore domain potassium channels in rat mesenteric and pulmonary arteries","volume":"142","author":"Gardener","year":"2004","journal-title":"Br. J. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e006465","DOI":"10.1161\/JAHA.117.006465","article-title":"The Impact of Heterozygous KCNK3 Mutations Associated With Pulmonary Arterial Hypertension on Channel Function and Pharmacological Recovery","volume":"6","author":"Bohnen","year":"2017","journal-title":"J. Am. Heart Assoc."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1016\/j.chest.2016.11.014","article-title":"EIF2AK4 Mutations in Patients Diagnosed With Pulmonary Arterial Hypertension","volume":"151","author":"Best","year":"2017","journal-title":"Chest"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Higasa, K., Ogawa, A., Terao, C., Shimizu, M., Kosugi, S., Yamada, R., Date, H., Matsubara, H., and Matsuda, F. (2017). A burden of rare variants in BMPR2 and KCNK3 contributes to a risk of familial pulmonary arterial hypertension. BMC Pulm. Med., 17.","DOI":"10.1186\/s12890-017-0400-z"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1016\/j.recesp.2016.03.031","article-title":"Molecular Analysis of BMPR2, TBX4, and KCNK3 and Genotype-Phenotype Correlations in Spanish Patients and Families With Idiopathic and Hereditary Pulmonary Arterial Hypertension","volume":"69","author":"Navas","year":"2016","journal-title":"Rev. Esp. Cardiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1161\/CIRCULATIONAHA.115.020951","article-title":"Potassium Channel Subfamily K Member 3 (KCNK3) Contributes to the Development of Pulmonary Arterial Hypertension","volume":"133","author":"Antigny","year":"2016","journal-title":"Circulation"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1161\/CIRCRESAHA.119.314793","article-title":"Characterization of Kcnk3-Mutated Rat, a Novel Model of Pulmonary Hypertension","volume":"125","author":"Lambert","year":"2019","journal-title":"Circ. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3231","DOI":"10.1113\/jphysiol.2011.206748","article-title":"Contractile and electrophysiological properties of pulmonary artery smooth muscle are not altered in TASK-1 knockout mice","volume":"589","author":"Manoury","year":"2011","journal-title":"J. Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1161\/HYPERTENSIONAHA.114.03406","article-title":"TWIK-2 channel deficiency leads to pulmonary hypertension through a rho-kinase-mediated process","volume":"64","author":"Pandit","year":"2014","journal-title":"Hypertension"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1097\/MOH.0000000000000239","article-title":"Endothelial functions of platelet\/endothelial cell adhesion molecule-1 (CD31)","volume":"23","author":"Lertkiatmongkol","year":"2016","journal-title":"Curr. Opin. Hematol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1161\/01.RES.0000021432.70309.28","article-title":"Mature vascular endothelium can give rise to smooth muscle cells via endothelial-mesenchymal transdifferentiation: In vitro analysis","volume":"90","author":"Frid","year":"2002","journal-title":"Circ. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1161\/CIRCULATIONAHA.114.008750","article-title":"Endothelial-to-mesenchymal transition in pulmonary hypertension","volume":"131","author":"Ranchoux","year":"2015","journal-title":"Circulation"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1783","DOI":"10.1161\/CIRCULATIONAHA.115.020617","article-title":"In Pulmonary Arterial Hypertension, Reduced BMPR2 Promotes Endothelial-to-Mesenchymal Transition via HMGA1 and Its Target Slug","volume":"133","author":"Hopper","year":"2016","journal-title":"Circulation"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1186\/s12931-020-01444-7","article-title":"In vivo miR-138-5p inhibition alleviates monocrotaline-induced pulmonary hypertension and normalizes pulmonary KCNK3 and SLC45A3 expression","volume":"21","author":"Courboulin","year":"2020","journal-title":"Respir. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"173618","DOI":"10.1016\/j.ejphar.2020.173618","article-title":"Down-regulation of lncRNA Gas5 promotes hypoxia-induced pulmonary arterial smooth muscle cell proliferation by regulating KCNK3 expression","volume":"889","author":"Hao","year":"2020","journal-title":"Eur. J. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"117419","DOI":"10.1016\/j.lfs.2020.117419","article-title":"Inhibition of RELM-beta prevents hypoxia-induced overproliferation of human pulmonary artery smooth muscle cells by reversing PLC-mediated KCNK3 decline","volume":"246","author":"Han","year":"2020","journal-title":"Life Sci."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Le Ribeuz, H., Dumont, F., Ruellou, G., Lambert, M., Balliau, T., Quatredeniers, M., Girerd, B., Cohen-Kaminsky, S., Mercier, O., and Yen-Nicolay, S. (2020). Proteomic Analysis of KCNK3 Loss of Expression Identified Dysregulated Pathways in Pulmonary Vascular Cells. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21197400"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"West, J.D., Austin, E.D., Rizzi, E.M., Yan, L., Tanjore, H., Crabtree, A.L., Moore, C.S., Muthian, G., Carrier, E.J., and Jacobson, D.A. (2021). KCNK3 Mutation Causes Altered Immune Function in Pulmonary Arterial Hypertension Patients and Mouse Models. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22095014"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.cardiores.2007.02.025","article-title":"The acid-sensitive potassium channel TASK-1 in rat cardiac muscle","volume":"75","author":"Putzke","year":"2007","journal-title":"Cardiovasc. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.33594\/000000083","article-title":"Identification of the A293 (AVE1231) Binding Site in the Cardiac Two-Pore-Domain Potassium Channel TASK-1: A Common Low Affinity Antiarrhythmic Drug Binding Site","volume":"52","author":"Wiedmann","year":"2019","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"13977","DOI":"10.1074\/jbc.M111.227884","article-title":"A specific two-pore domain potassium channel blocker defines the structure of the TASK-1 open pore","volume":"286","author":"Streit","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3968","DOI":"10.1016\/j.bmcl.2014.06.032","article-title":"Potent and selective inhibitors of the TASK-1 potassium channel through chemical optimization of a bis-amide scaffold","volume":"24","author":"Flaherty","year":"2014","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1113\/JP277275","article-title":"Characterization and regulation of wild-type and mutant TASK-1 two pore domain potassium channels indicated in pulmonary arterial hypertension","volume":"597","author":"Cunningham","year":"2019","journal-title":"J. Physiol. Lond."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"16650","DOI":"10.1074\/jbc.M000030200","article-title":"TASK-3, a novel tandem pore domain acid-sensitive K+ channel\u2014An extracellular histidine as pH sensor","volume":"275","author":"Rajan","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"9340","DOI":"10.1074\/jbc.275.13.9340","article-title":"TASK-3, a new member of the tandem pore K+ channel family","volume":"275","author":"Kim","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"5426","DOI":"10.1074\/jbc.M107138200","article-title":"Formation of functional heterodimers between the TASK-1 and TASK-3 two-pore domain potassium channel subunits","volume":"277","author":"Czirjak","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"6693","DOI":"10.1523\/JNEUROSCI.1408-04.2004","article-title":"Motoneurons express heteromeric TWIK-related acid-sensitive K+ (TASK) channels containing TASK-1 (KCNK3) and TASK-3 (KCNK9) subunits","volume":"24","author":"Berg","year":"2004","journal-title":"J. Neurosci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.yjmcc.2015.01.017","article-title":"TASK-1 and TASK-3 may form heterodimers in human atrial cardiomyocytes","volume":"81","author":"Rinne","year":"2015","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2963","DOI":"10.1113\/jphysiol.2009.171181","article-title":"Heteromeric TASK-1\/TASK-3 is the major oxygen-sensitive background K+ channel in rat carotid body glomus cells","volume":"587","author":"Kim","year":"2009","journal-title":"J. Physiol.-London"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1038\/nature04711","article-title":"KATP channels as molecular sensors of cellular metabolism","volume":"440","author":"Nichols","year":"2006","journal-title":"Nature"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1152\/physrev.00003.2015","article-title":"KATP Channels in the Cardiovascular System","volume":"96","author":"Foster","year":"2016","journal-title":"Physiol. Rev."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1098\/rstb.2008.0142","article-title":"Review. SUR1: A unique ATP-binding cassette protein that functions as an ion channel regulator","volume":"364","author":"Aittoniemi","year":"2009","journal-title":"Philos. Trans. R. Soc. Lond. B Biol. Sci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.1126\/science.270.5239.1166","article-title":"Reconstitution of IKATP: An inward rectifier subunit plus the sulfonylurea receptor","volume":"270","author":"Inagaki","year":"1995","journal-title":"Science"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1113\/jphysiol.1997.sp021843","article-title":"Properties of cloned ATP-sensitive K+ currents expressed in Xenopus oocytes","volume":"498","author":"Gribble","year":"1997","journal-title":"J. Physiol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"e32481","DOI":"10.7554\/eLife.32481","article-title":"Molecular structure of human KATP in complex with ATP and ADP","volume":"6","author":"Lee","year":"2017","journal-title":"eLife"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1161\/HYPERTENSIONAHA.119.12992","article-title":"Pulmonary Hypertension and ATP-Sensitive Potassium Channels","volume":"74","author":"McClenaghan","year":"2019","journal-title":"Hypertension"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1016\/S0735-1097(00)01195-5","article-title":"Alterations in potassium channel gene expression in atria of patients with persistent and paroxysmal atrial fibrillation: Differential regulation of protein and mRNA levels for K+ channels","volume":"37","author":"Brundel","year":"2001","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1458","DOI":"10.1161\/CIRCRESAHA.108.178186","article-title":"Differential structure of atrial and ventricular KATP: Atrial KATP channels require SUR1","volume":"103","author":"Flagg","year":"2008","journal-title":"Circ. Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1161\/01.RES.83.11.1132","article-title":"Reconstituted human cardiac KATP channels: Functional identity with the native channels from the sarcolemma of human ventricular cells","volume":"83","author":"Babenko","year":"1998","journal-title":"Circ. Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1161\/CIRCEP.111.964643","article-title":"Unique properties of the ATP-sensitive K(+) channel in the mouse ventricular cardiac conduction system","volume":"4","author":"Bao","year":"2011","journal-title":"Circ. Arrhythm. Electrophysiol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1016\/j.yjmcc.2004.05.022","article-title":"K ATP channels of primary human coronary artery endothelial cells consist of a heteromultimeric complex of Kir6.1, Kir6.2, and SUR2B subunits","volume":"37","author":"Yoshida","year":"2004","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"15135","DOI":"10.1038\/s41598-020-72089-1","article-title":"Characterization of rare ABCC8 variants identified in Spanish pulmonary arterial hypertension patients","volume":"10","author":"Tenorio","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1007\/s12325-008-0049-3","article-title":"Pulmonary hypertension, heart failure and neutropenia due to diazoxide therapy","volume":"25","author":"Yildizdas","year":"2008","journal-title":"Adv. Ther."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1056\/NEJM198001103020204","article-title":"Diazoxide in primary pulmonary hypertension","volume":"302","author":"Klinke","year":"1980","journal-title":"N. Engl. J. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1136\/hrt.57.2.207","article-title":"Reversibility of primary pulmonary hypertension during six years of treatment with oral diazoxide","volume":"57","author":"Chan","year":"1987","journal-title":"Br. Heart J."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1165\/ajrcmb.26.1.4622","article-title":"The molecular composition of K(ATP) channels in human pulmonary artery smooth muscle cells and their modulation by growth","volume":"26","author":"Cui","year":"2002","journal-title":"Am. J. Respir. Cell. Mol. Biol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1165\/rcmb.2021-0180OC","article-title":"SUR1 As a New Therapeutic Target for Pulmonary Arterial Hypertension","volume":"66","author":"Masson","year":"2022","journal-title":"Am. J. Respir. Cell. Mol. Biol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3655","DOI":"10.1074\/jbc.M112.428219","article-title":"The sulfonylurea receptor 1 (Sur1)-transient receptor potential melastatin 4 (Trpm4) channel","volume":"288","author":"Woo","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1007\/s00424-013-1250-z","article-title":"TRPM4 channels in smooth muscle function","volume":"465","author":"Earley","year":"2013","journal-title":"Pflugers Arch."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"L1267","DOI":"10.1152\/ajplung.00515.2005","article-title":"Functional expression of transient receptor potential melastatin- and vanilloid-related channels in pulmonary arterial and aortic smooth muscle","volume":"290","author":"Yang","year":"2006","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"8746","DOI":"10.1074\/jbc.M111.336131","article-title":"On potential interactions between non-selective cation channel TRPM4 and sulfonylurea receptor SUR1","volume":"287","author":"Wang","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"4905","DOI":"10.1074\/jbc.M807638200","article-title":"17beta-Estradiol modulates apoptosis in pancreatic beta-cells by specific involvement of the sulfonylurea receptor (SUR) isoform SUR1","volume":"284","author":"Ackermann","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"3347","DOI":"10.1074\/jbc.M608216200","article-title":"Resveratrol binds to the sulfonylurea receptor (SUR) and induces apoptosis in a SUR subtype-specific manner","volume":"282","author":"Hambrock","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1113\/jphysiol.1985.sp015721","article-title":"Properties of adenosine-triphosphate-regulated potassium channels in guinea-pig ventricular cells","volume":"363","author":"Kakei","year":"1985","journal-title":"J. Physiol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/0014-5793(86)81532-0","article-title":"Intracellular ADP activates K+ channels that are inhibited by ATP in an insulin-secreting cell line","volume":"208","author":"Dunne","year":"1986","journal-title":"FEBS Lett."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1007\/BF01995702","article-title":"Interaction of diazoxide, tolbutamide and ATP4- on nucleotide-dependent K+ channels in an insulin-secreting cell line","volume":"99","author":"Dunne","year":"1987","journal-title":"J. Membr. Biol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1126\/science.7716547","article-title":"Cloning of the beta cell high-affinity sulfonylurea receptor: A regulator of insulin secretion","volume":"268","author":"Nichols","year":"1995","journal-title":"Science"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1124\/mol.55.6.1060","article-title":"Stoichiometry of sulfonylurea-induced ATP-sensitive potassium channel closure","volume":"55","author":"Dorschner","year":"1999","journal-title":"Mol. Pharmacol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.pharmthera.2013.06.007","article-title":"Multiplicity of effectors of the cardioprotective agent, diazoxide","volume":"140","author":"Coetzee","year":"2013","journal-title":"Pharmacol. Ther."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"545638","DOI":"10.3389\/fendo.2020.545638","article-title":"Possible New Strategies for the Treatment of Congenital Hyperinsulinism","volume":"11","author":"Sikimic","year":"2020","journal-title":"Front. Endocrinol."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Barros, F., Pardo, L.A., Dom\u00ednguez, P., Sierra, L.M., and de la Pe\u00f1a, P. (2019). New Structures and Gating of Voltage-Dependent Potassium (Kv) Channels and Their Relatives: A Multi-Domain and Dynamic Question. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20020248"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1161\/01.RES.77.2.370","article-title":"Voltage-gated K+ currents regulate resting membrane potential and [Ca2+]i in pulmonary arterial myocytes","volume":"77","author":"Yuan","year":"1995","journal-title":"Circ. Res."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1152\/physrev.00020.2009","article-title":"Ancillary subunits associated with voltage-dependent K+ channels","volume":"90","author":"Pongs","year":"2010","journal-title":"Physiol. Rev."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1161\/01.RES.0000137173.42723.fb","article-title":"Preferential expression and function of voltage-gated, O2-sensitive K+ channels in resistance pulmonary arteries explains regional heterogeneity in hypoxic pulmonary vasoconstriction: Ionic diversity in smooth muscle cells","volume":"95","author":"Archer","year":"2004","journal-title":"Circ. Res."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"C970","DOI":"10.1152\/ajpcell.2001.280.4.C970","article-title":"Activation of K+ channels induces apoptosis in vascular smooth muscle cells","volume":"280","author":"Krick","year":"2001","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"C715","DOI":"10.1152\/ajpcell.00050.2004","article-title":"Overexpression of human KCNA5 increases IK(V) and enhances apoptosis","volume":"287","author":"Brevnova","year":"2004","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"L887","DOI":"10.1152\/ajplung.2001.281.4.L887","article-title":"Augmented K(+) currents and mitochondrial membrane depolarization in pulmonary artery myocyte apoptosis","volume":"281","author":"Krick","year":"2001","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"C157","DOI":"10.1152\/ajpcell.2001.281.1.C157","article-title":"Bcl-2 decreases voltage-gated K+ channel activity and enhances survival in vascular smooth muscle cells","volume":"281","author":"Ekhterae","year":"2001","journal-title":"Am. J. Physiol. Cell. Physiol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1080\/10739680600930222","article-title":"The role of k+ channels in determining pulmonary vascular tone, oxygen sensing, cell proliferation, and apoptosis: Implications in hypoxic pulmonary vasoconstriction and pulmonary arterial hypertension","volume":"13","author":"Moudgil","year":"2006","journal-title":"Microcirculation"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"2319","DOI":"10.1172\/JCI333","article-title":"Molecular identification of the role of voltage-gated K+ channels, Kv1.5 and Kv2.1, in hypoxic pulmonary vasoconstriction and control of resting membrane potential in rat pulmonary artery myocytes","volume":"101","author":"Archer","year":"1998","journal-title":"J. Clin. Investig."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"2630","DOI":"10.1161\/CIRCULATIONAHA.105.609008","article-title":"An abnormal mitochondrial-hypoxia inducible factor-1alpha-Kv channel pathway disrupts oxygen sensing and triggers pulmonary arterial hypertension in fawn hooded rats: Similarities to human pulmonary arterial hypertension","volume":"113","author":"Bonnet","year":"2006","journal-title":"Circulation"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1111\/j.1749-6632.2009.05040.x","article-title":"Hypoxia selectively inhibits KCNA5 channels in pulmonary artery smooth muscle cells","volume":"1177","author":"Firth","year":"2009","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1161\/01.RES.0000216858.04599.e1","article-title":"Serotonin inhibits voltage-gated K+ currents in pulmonary artery smooth muscle cells: Role of 5-HT2A receptors, caveolin-1, and KV1.5 channel internalization","volume":"98","author":"Cogolludo","year":"2006","journal-title":"Circ. Res."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"2089","DOI":"10.1126\/science.274.5295.2089","article-title":"Association of Src tyrosine kinase with a human potassium channel mediated by SH3 domain","volume":"274","author":"Holmes","year":"1996","journal-title":"Science"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"4073","DOI":"10.1091\/mbc.e03-11-0788","article-title":"Endocytosis as a mechanism for tyrosine kinase-dependent suppression of a voltage-gated potassium channel","volume":"15","author":"Nesti","year":"2004","journal-title":"Mol. Biol. Cell"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1161\/01.RES.0000095245.97945.FE","article-title":"Thromboxane A2-induced inhibition of voltage-gated K+ channels and pulmonary vasoconstriction: Role of protein kinase Czeta","volume":"93","author":"Cogolludo","year":"2003","journal-title":"Circ. Res."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"L841","DOI":"10.1152\/ajplung.00158.2005","article-title":"BMP signaling controls PASMC KV channel expression in vitro and in vivo","volume":"290","author":"Young","year":"2006","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"L993","DOI":"10.1152\/ajplung.00191.2005","article-title":"Bone morphogenetic protein-2 upregulates expression and function of voltage-gated K+ channels in human pulmonary artery smooth muscle cells","volume":"291","author":"Fantozzi","year":"2006","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"L740","DOI":"10.1152\/ajplung.00284.2002","article-title":"Bone morphogenetic proteins induce apoptosis in human pulmonary vascular smooth muscle cells","volume":"285","author":"Zhang","year":"2003","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1161\/01.RES.0000126047.82846.20","article-title":"Pulmonary hypertension in transgenic mice expressing a dominant-negative BMPRII gene in smooth muscle","volume":"94","author":"West","year":"2004","journal-title":"Circ. Res."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"3093","DOI":"10.1002\/art.27607","article-title":"Association of a KCNA5 gene polymorphism with systemic sclerosis-associated pulmonary arterial hypertension in the European Caucasian population","volume":"62","author":"Wipff","year":"2010","journal-title":"Arthr. Rheum."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"C1837","DOI":"10.1152\/ajpcell.00405.2006","article-title":"Function of Kv1.5 channels and genetic variations of KCNA5 in patients with idiopathic pulmonary arterial hypertension","volume":"292","author":"Remillard","year":"2007","journal-title":"Am. J. Physiol. Cell. Physiol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.gene.2018.09.020","article-title":"5-HTT, BMPR2, EDN1, ENG, KCNA5 gene polymorphisms and susceptibility to pulmonary arterial hypertension: A meta-analysis","volume":"680","author":"Jiao","year":"2019","journal-title":"Gene"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/S2213-2600(18)30409-0","article-title":"Genetic determinants of risk in pulmonary arterial hypertension: International genome-wide association studies and meta-analysis","volume":"7","author":"Rhodes","year":"2019","journal-title":"Lancet Respir. Med."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"2185","DOI":"10.1093\/hmg\/ddl143","article-title":"Kv1.5 channelopathy due to KCNA5 loss-of-function mutation causes human atrial fibrillation","volume":"15","author":"Olson","year":"2006","journal-title":"Hum. Mol. Genet."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1161\/01.RES.0000096362.60730.AE","article-title":"Kv1.5 is an important component of repolarizing K+ current in canine atrial myocytes","volume":"93","author":"Fedida","year":"2003","journal-title":"Circ. Res."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1016\/S0006-3495(01)75749-9","article-title":"A Model for 4-Aminopyridine Action on K Channels: Similarities to Tetraethylammonium Ion Action","volume":"81","author":"Armstrong","year":"2001","journal-title":"Biophys. J."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1038\/nrd2983","article-title":"Voltage-gated potassium channels as therapeutic targets","volume":"8","author":"Wulff","year":"2009","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1111\/j.1476-5381.2009.00283.x","article-title":"Treatment with the Kv7 potassium channel activator flupirtine is beneficial in two independent mouse models of pulmonary hypertension","volume":"157","author":"Morecroft","year":"2009","journal-title":"Br. J. Pharmacol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1161\/hc0202.101974","article-title":"Dichloroacetate, a metabolic modulator, prevents and reverses chronic hypoxic pulmonary hypertension in rats: Role of increased expression and activity of voltage-gated potassium channels","volume":"105","author":"Michelakis","year":"2002","journal-title":"Circulation"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"2131","DOI":"10.1111\/bph.14662","article-title":"Activation of K(v) 7 channels as a novel mechanism for NO\/cGMP-induced pulmonary vasodilation","volume":"176","author":"Barreira","year":"2019","journal-title":"Br. J. Pharmacol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"662.616","DOI":"10.1096\/fasebj.29.1_supplement.662.16","article-title":"miRNA-29b Directly Downregulates K+ Channel Expression and Function in IPAH-PASMC","volume":"29","author":"Ayon","year":"2015","journal-title":"FASEB J."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"2037","DOI":"10.1161\/01.CIR.0000062688.76508.B3","article-title":"In vivo gene transfer of the O2-sensitive potassium channel Kv1.5 reduces pulmonary hypertension and restores hypoxic pulmonary vasoconstriction in chronically hypoxic rats","volume":"107","author":"Pozeg","year":"2003","journal-title":"Circulation"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/12\/10\/1341\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:37:05Z","timestamp":1760143025000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/12\/10\/1341"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,22]]},"references-count":112,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["biom12101341"],"URL":"https:\/\/doi.org\/10.3390\/biom12101341","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,22]]}}}