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Characterization and regulation of wild-type and mutant TASK-1 two pore domain potassium channels indicated in pulmonary arterial hypertension.

Cunningham, Kevin Peter, Holden, Robyn G, Escribano-Subias, Pilar M, Cogolludo, Angel, Veale, Emma L., Mathie, Alistair (2019) Characterization and regulation of wild-type and mutant TASK-1 two pore domain potassium channels indicated in pulmonary arterial hypertension. The Journal of physiology, 597 (4). pp. 1087-1101. ISSN 1469-7793. (doi:10.1113/JP277275) (Access to this publication is currently restricted. You may be able to access a copy if URLs are provided) (KAR id:75879)

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Abstract

KEY POINTS

The 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.

ABSTRACT

Pulmonary 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.

Item Type: Article
DOI/Identification number: 10.1113/JP277275
Subjects: Q Science > QP Physiology (Living systems)
Divisions: Faculties > Sciences > Medway School of Pharmacy
Depositing User: Emma Veale
Date Deposited: 19 Aug 2019 21:24 UTC
Last Modified: 23 Jan 2020 04:16 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/75879 (The current URI for this page, for reference purposes)
Veale, Emma L.: https://orcid.org/0000-0002-6778-9929
Mathie, Alistair: https://orcid.org/0000-0001-6094-2890
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