PhD Scientific Days 2023

Molecular Sciences I.

Role of the TREK-1 Potassium Channel in Pulmonary Arterial Resting Tone

Előadó neve

Csáki, Réka

Neptun code

KA84WY

Előadó munkahelye

Semmelweis University

Előadó telefonszáma

+36304100841

Előadó e-mail címe

csaki.reka@phd.semmelweis.hu

Az előadás címe

Role of the TREK-1 Potassium Channel in Pulmonary Arterial Resting Tone

Szerző(k) neve és munkahelye

Réka Csáki1
1 Semmelweis University, Department of Physiology, Budapest

Bemutatás módja

Szóbeli

Szekció

Molecular Sciences I.

Language of the presentation

English

Preferred session

Molecular Sciences

Összefoglaló szövege

Introduction:
Various potassium channels are expressed in the vessels of the pulmonary circulation, including the smooth muscle cells of the small pulmonary arteries (PASMCs). They hyperpolarize and relax the SMCs thereby contribute to the maintenance of the reduced/low vascular tone. Depolarization from the normal resting membrane potential of PASMCs leads to vasoconstriction, vascular remodelling and increased pulmonary vascular resistance. As a consequence, pulmonary arterial hypertension (PAH) and eventually right heart failure develops, which are serious and often fatal diseases. Downregulation of potassium channel activity in PAH patients may significantly contribute to the observed electrophysiological changes of PASMCs. One of the background (K2P) potassium channels, TASK-1, has become the focus of interest as its dominant negative mutation has been associated with familial form of PAH.

Aims:
Our aim was to identify further potassium channel/s which might be important in the maintenance of the hyperpolarized resting membrane potential of PASMCs in healthy individuals, and to investigate whether (and to what extent) their altered activity could be a pathogenic factor in PAH. In this process we also tested pharmacological agents known to act on the relevant potassium channel considering also the possibility that a channel activating, cell hyperpolarizing drug might have beneficial effect in PAH.

Method:
RT-qPCR analysis revealed TREK-1 to be the most abundantly expressed K2P channel in both donor and IPAH PASMCs, with moderately reduced expression level in the IPAH group. The functional significance of TREK-1 was addressed by patch clamping; measuring the TREK-1 derived leak potassium current of PASMCs and the effect of its modulation on the membrane potential. The effect of TREK-1 activity on the intracellular Ca2+ signalling was examined by Ca2+ imaging.

Results:
As expected, the resting membrane potential of IPAH PASMCs was depolarized compared to donor cells. We found a significant activation of the background potassium current both in the donor and IPAH patients by the specific TREK activator, ML-335. Pharmacological inhibition or siRNA silencing of TREK-1 in donor PASMCs depolarized their membrane potential. Application of ML-335 hyperpolarized donor PASMCs and normalized the membrane potential of IPAH PASMCs. Consistent with the effects on the resting membrane potential, inhibition of TREK-1 augmented, while activation of the channel attenuated the calcium response to extracellular acidification.

Conclusion:
Our results suggest that TREK-1 might represent a new pharmacological target for the treatment of IPAH.

Funding:
Semmelweis 250+ Excellence Fellowship

University and Doctoral School

Semmelweis University, Doctoral School of Molecular Medicine

Supervisor

Péter Enyedi M.D., D.Sc.

Publication of my abstract

I do not give consent to the publication of my abstract on the website of the congress.

Kind

Szabad

Status

elfogadva

Accepted presentation method

szóbeli

Előadás fájl jóváhagyás

nem rendelkezett róla

Előadó

7416

Start

10:45

End

11:00

Authors (legacy)

Réka Csáki1
1 Semmelweis University, Department of Physiology, Budapest