@article{REAL225005,
          volume = {181},
          number = {19},
          author = {R{\'e}ka Cs{\'a}ki and Chandran Nagaraj and J{\'a}nos Alm{\'a}ssy and Mohammad Ali Khozeimeh and Dusan Jeremic and Horst Olschewski and Alice Dobolyi and Konrad Hoetzenecker and Andrea Olschewski and P{\'e}ter Enyedi and Mikl{\'o}s Lengyel},
            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.},
           title = {The TREK-1 potassium channel is a potential pharmacological target for vasorelaxation in pulmonary hypertension},
         journal = {BRITISH JOURNAL OF PHARMACOLOGY},
           pages = {3576--3593},
            year = {2024},
        keywords = {Spadin; TREK-1; pulmonary arterial hypertension (PAH); ML-335; pulmonary arterial smooth muscle cells (PASMC);},
             url = {https://real.mtak.hu/225005/},
        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.}
}