eprintid: 225005 rev_number: 8 eprint_status: archive userid: 958 dir: disk0/00/22/50/05 datestamp: 2025-09-23 13:04:05 lastmod: 2025-09-23 13:04:05 status_changed: 2025-09-23 13:04:05 type: article metadata_visibility: show contact_email: csaki.reka@phd.semmelweis.hu sword_depositor: 958 creators_name: Csáki, Réka creators_name: Nagaraj, Chandran creators_name: Almássy, János creators_name: Khozeimeh, Mohammad Ali creators_name: Jeremic, Dusan creators_name: Olschewski, Horst creators_name: Dobolyi, Alice creators_name: Hoetzenecker, Konrad creators_name: Olschewski, Andrea creators_name: Enyedi, Péter creators_name: Lengyel, Miklós creators_orcid: creators_orcid: creators_orcid: creators_orcid: creators_orcid: creators_orcid: creators_orcid: creators_orcid: creators_orcid: creators_orcid: 0000-0001-9541-0712 creators_orcid: 0000-0001-6382-6369 corp_creators: Élettani Intézet SE / AOK / I ÉI [2000-] title: The TREK-1 potassium channel is a potential pharmacological target for vasorelaxation in pulmonary hypertension ispublished: pub subjects: R1 full_text_status: public keywords: Spadin; TREK-1; pulmonary arterial hypertension (PAH); ML-335; pulmonary arterial smooth muscle cells (PASMC); note: Funding Agency and Grant Number: Nemzeti Kutatsi Fejlesztsi s Innovcis Hivatal Funding text: The skilful technical assistance provided by Elisabeth Blanz is much appreciated. abstract: 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 date_type: published publication: BRITISH JOURNAL OF PHARMACOLOGY volume: 181 number: 19 pagerange: 3576-3593 id_number: MTMT:34911313 10.1111/bph.16426 refereed: TRUE issn: 0007-1188 official_url: https://doi.org/10.1111/bph.16426 funders: Bolyai János Kutatási Ösztöndíj fp7_project: no fp7_type: info:eu-repo/semantics/article citation: 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 document_url: https://real.mtak.hu/225005/1/BritishJPharmacology-2024-Csaki-TheTREK1potassiumchannelisapotentialpharmacologicaltargetfor1.pdf document_url: https://real.mtak.hu/225005/7/bph16426-toc-0001-m.jpg