http://purl.uniprot.org/citations/30365877 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
http://purl.uniprot.org/citations/30365877 | http://www.w3.org/2000/01/rdf-schema#comment | "Key pointsThe TASK-1 channel gene (KCNK3) has been identified as a possible disease-causing gene in heritable pulmonary arterial hypertension (PAH). In the present study, we show that novel mutated TASK-1 channels, seen in PAH patients, have a substantially reduced current compared to wild-type TASK-1 channels. These mutated TASK-1 channels are located at the plasma membrane to the same degree as wild-type TASK-1 channels. ONO-RS-082 and alkaline pH 8.4 both activate TASK-1 channels but do not recover current through mutant TASK-1 channels. We show that the guanylate cyclase activator, riociguat, a novel treatment for PAH, enhances current through TASK-1 channels but does not recover current through mutant TASK-1 channels.AbstractPulmonary arterial hypertension (PAH) affects ∼15-50 people per million. KCNK3, the gene that encodes the two pore domain potassium channel TASK-1 (K2P3.1), has been identified as a possible disease-causing gene in heritable PAH. Recently, two new mutations have been identified in KCNK3 in PAH patients: G106R and L214R. The present study aimed to characterize the functional properties and regulation of wild-type (WT) and mutated TASK-1 channels and determine how these might contribute to PAH and its treatment. Currents through WT and mutated human TASK-1 channels transiently expressed in tsA201 cells were measured using whole-cell patch clamp electrophysiology. Localization of fluorescence-tagged channels was visualized using confocal microscopy and quantified with in-cell and on-cell westerns. G106R or L214R mutated channels were located at the plasma membrane to the same degree as WT channels; however, their current was markedly reduced compared to WT TASK-1 channels. Functional current through these mutated channels could not be restored using activators of WT TASK-1 channels (pH 8.4, ONO-RS-082). The guanylate cyclase activator, riociguat, enhanced current through WT TASK-1 channels; however, similar to the other activators investigated, riociguat did not have any effect on current through mutated TASK-1 channels. Thus, novel mutations in TASK-1 seen in PAH substantially alter the functional properties of these channels. Current through these channels could not be restored by activators of TASK-1 channels. Riociguat enhancement of current through TASK-1 channels could contribute to its therapeutic benefit in the treatment of PAH."xsd:string |
http://purl.uniprot.org/citations/30365877 | http://purl.org/dc/terms/identifier | "doi:10.1113/jp277275"xsd:string |
http://purl.uniprot.org/citations/30365877 | http://purl.uniprot.org/core/author | "Cogolludo A."xsd:string |
http://purl.uniprot.org/citations/30365877 | http://purl.uniprot.org/core/author | "Mathie A."xsd:string |
http://purl.uniprot.org/citations/30365877 | http://purl.uniprot.org/core/author | "Veale E.L."xsd:string |
http://purl.uniprot.org/citations/30365877 | http://purl.uniprot.org/core/author | "Cunningham K.P."xsd:string |
http://purl.uniprot.org/citations/30365877 | http://purl.uniprot.org/core/author | "Escribano-Subias P.M."xsd:string |
http://purl.uniprot.org/citations/30365877 | http://purl.uniprot.org/core/author | "Holden R.G."xsd:string |
http://purl.uniprot.org/citations/30365877 | http://purl.uniprot.org/core/date | "2019"xsd:gYear |
http://purl.uniprot.org/citations/30365877 | http://purl.uniprot.org/core/name | "J Physiol"xsd:string |
http://purl.uniprot.org/citations/30365877 | http://purl.uniprot.org/core/pages | "1087-1101"xsd:string |
http://purl.uniprot.org/citations/30365877 | http://purl.uniprot.org/core/title | "Characterization and regulation of wild-type and mutant TASK-1 two pore domain potassium channels indicated in pulmonary arterial hypertension."xsd:string |
http://purl.uniprot.org/citations/30365877 | http://purl.uniprot.org/core/volume | "597"xsd:string |
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http://purl.uniprot.org/citations/30365877 | http://xmlns.com/foaf/0.1/primaryTopicOf | https://pubmed.ncbi.nlm.nih.gov/30365877 |
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