relation: https://real.mtak.hu/225005/
title: The TREK-1 potassium channel is a potential pharmacological target for vasorelaxation in pulmonary hypertension
creator: Csáki, Réka
creator: Nagaraj, Chandran
creator: Almássy, János
creator: Khozeimeh, Mohammad Ali
creator: Jeremic, Dusan
creator: Olschewski, Horst
creator: Dobolyi, Alice
creator: Hoetzenecker, Konrad
creator: Olschewski, Andrea
creator: Enyedi, Péter
creator: Lengyel, Miklós
subject: R1 Medicine (General) / orvostudomány általában
description: Background and purpose  Pulmonary arterial hypertension (PAH) is a progressive disease in which chronic membrane potential (Em) depolarisation of the pulmonary arterial smooth muscle cells (PASMCs) causes calcium overload, a key pathological alteration. Under resting conditions, the negative Em is mainly set by two pore domain potassium (K2P) channels, of which the TASK-1 has been extensively investigated.    Experimental Approach  Ion channel currents and membrane potential of primary cultured human(h) PASMCs were measured using the voltage- and current clamp methods. Intracellular [Ca2+] was monitored using fluorescent microscopy. Pulmonary BP and vascular tone measurements were also performed ex vivo using a rat PAH model.    Key Results  TREK-1 was the most abundantly expressed K2P in hPASMCs of healthy donors and idiopathic(I) PAH patients. Background K+-current was similar in hPASMCs for both groups and significantly enhanced by the TREK activator ML-335. In donor hPASMCs, siRNA silencing or pharmacological inhibition of TREK-1 caused depolarisation, reminiscent of the electrophysiological phenotype of idiopathic PAH. ML-335 hyperpolarised donor hPASMCs and normalised the Em of IPAH hPASMCs. A close link was found between TREK-1 activity and intracellular Ca2+-signalling using a channel activator, ML-335, and an inhibitor, spadin. In the rat, ML-335 relaxed isolated pre-constricted pulmonary arteries and significantly decreased pulmonary arterial pressure in the isolated perfused lung.    Conclusions and Implications  These data suggest that TREK-1is a key factor in Em setting and Ca2+ homeostasis of hPASMC, and therefore, essential for maintenance of a low resting pulmonary vascular tone. Thus TREK-1 may represent a new therapeutic target for PAH.
date: 2024
type: Article
type: PeerReviewed
format: text
language: en
rights: cc_by
identifier: https://real.mtak.hu/225005/1/BritishJPharmacology-2024-Csaki-TheTREK1potassiumchannelisapotentialpharmacologicaltargetfor1.pdf
format: text
language: en
identifier: https://real.mtak.hu/225005/7/bph16426-toc-0001-m.jpg
identifier:   Csáki, Réka and Nagaraj, Chandran and Almássy, János and Khozeimeh, Mohammad Ali and Jeremic, Dusan and Olschewski, Horst and Dobolyi, Alice and Hoetzenecker, Konrad and Olschewski, Andrea and Enyedi, Péter and Lengyel, Miklós  (2024) The TREK-1 potassium channel is a potential pharmacological target for vasorelaxation in pulmonary hypertension.  BRITISH JOURNAL OF PHARMACOLOGY, 181 (19).  pp. 3576-3593.  ISSN 0007-1188     
relation: https://doi.org/10.1111/bph.16426
relation: MTMT:34911313 10.1111/bph.16426
type: info:eu-repo/semantics/article