The TREK-1 channel belongs to the TREK subfamily of two-pore domains channels that are activated by stretch and polyunsaturated fatty acids and inactivated by Protein Kinase A phosphorylation. The activation of this potassium channel must induce a hyperpolarization of the resting membrane potential and a shortening of the action potential duration in neurons and cardiac cells, two phenomena being beneficial for these tissues in pathological situations like ischemia-reperfusion. Surprisingly, the physiological role of TREK-1 in cardiac function has never been thoroughly investigated, very likely because of the lack of a specific inhibitor. However, possible roles have been unraveled in pathological situations such as atrial fibrillation worsened by heart failure, right ventricular outflow tract tachycardia or pulmonary arterial hypertension. The inhomogeneous distribution of TREK-1 channel within the heart reinforces the idea that this stretch-activated potassium channel might play a role in cardiac areas where the mechanical constraints are important and need a particular protection afforded by TREK-1. Consequently, the main purpose of this mini review is to discuss the possible role played by TREK -1 in physiological and pathophysiological conditions and its potential role in mechano-electrical feedback. Improved understanding of the role of TREK-1 in the heart may help the development of promising treatments for challenging cardiac diseases.

Oxylipins, small polar molecules derived from the peroxidation of polyunsaturated fatty acids (PUFAs), serve as biomarkers for many diseases and play crucial roles in human physiology and inflammation. Despite their significance, many non-enzymatic oxygenated metabolites of PUFAs (NEO-PUFAs) remain poorly reported, resulting in a lack of public datasets of experimental data and limiting their dereplication in further studies. To overcome this limitation, we constructed a high-resolution tandem mass spectrometry (MS/MS) dataset comprising pure NEO-PUFAs (both commercial and self-synthesized) and in vitro free radical-induced oxidation of diverse PUFAs. By employing molecular networking techniques with this dataset and the existent ones in public repositories, we successfully mapped a wide range of NEO-PUFAs, expanding the strategies for annotating oxylipins, and NEO-PUFAs and offering a novel workflow for profiling these molecules in biological samples.

The use of zebrafish to explore cardiac physiology has been widely adopted within the scientific community. Whether this animal model can be used to determine drug cardiac toxicity via electrocardiogram (ECG) analysis is still an ongoing question. Several reports indicate that the recording configuration severely affects the ECG waveforms and its derived-parameters, emphasizing the need for improved characterization. To address this problem, we recorded ECGs from adult zebrafish hearts in three different configurations (unexposed heart, exposed heart, and extracted heart) to identify the most reliable method to explore ECG recordings at baseline and in response to commonly used clinical therapies. We found that the exposed heart configuration provided the most reliable and reproducible ECG recordings of waveforms and intervals. We were unable to determine T wave morphology in unexposed hearts. In extracted hearts, ECG intervals were lengthened and P waves were unstable. However, in the exposed heart configuration, we were able to reliably record ECGs and subsequently establish the QT-RR relationship (Holzgrefe correction) in response to changes in heart rate.

TREK-1 is a mechanosensitive channel activated by polyunsaturated fatty acids (PUFAs). Its activation is supposed to be linked to changes in membrane tension following PUFAs insertion. Here, we compared the effect of 11 fatty acids and ML402 on TREK-1 channel activation using the whole cell and the inside-out configurations of the patch-clamp technique. Firstly, TREK-1 activation by PUFAs is variable and related to the variable constitutive activity of TREK-1. We observed no correlation between TREK-1 activation and acyl chain length or number of double bonds suggesting that the bilayer-couple hypothesis cannot explain by itself the activation of TREK-1 by PUFAs. The membrane fluidity measurement is not modified by PUFAs at 10 µM. The spectral shift analysis in TREK-1-enriched microsomes indicates a K_D,TREK1 at 44 µM of C22:6 n-3. PUFAs display the same activation and reversible kinetics than the direct activator ML402 and activate TREK-1 in both whole-cell and inside-out configurations of patch-clamp suggesting that the binding site of PUFAs is accessible from both sides of the membrane, as for ML402. Finally, we proposed a two steps mechanism: first, insertion into the membrane, with no fluidity or curvature modifications at 10 µM, and then interaction with TREK-1 channel to open it.