%A Réka Csáki
%A Chandran Nagaraj
%A János Almássy
%A Mohammad Ali Khozeimeh
%A Dusan Jeremic
%A Horst Olschewski
%A Alice Dobolyi
%A Konrad Hoetzenecker
%A Andrea Olschewski
%A Péter Enyedi
%A Miklós Lengyel
%O Funding Agency and Grant Number: Nemzeti Kutatsi Fejlesztsi s Innovcis Hivatal
            Funding text: The skilful technical assistance provided by Elisabeth Blanz is much appreciated.
%J BRITISH JOURNAL OF PHARMACOLOGY
%T The TREK-1 potassium channel is a potential pharmacological target for vasorelaxation in pulmonary hypertension
%X 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.
%N 19
%K Spadin; TREK-1; pulmonary arterial hypertension (PAH); ML-335; pulmonary arterial smooth muscle cells (PASMC);
%P 3576-3593
%V 181
%D 2024
%R MTMT:34911313 10.1111/bph.16426
%L REAL225005