de la Cruz, A. | Search bioRxiv

bioRxiv2024

RvD1 and LXA4 inhibitory effects on cardiac voltage-gated potassium channels

AimsThe resolution of inflammation is modulated by specialized pro-resolving lipid mediators (SPMs), which can be modified in some cardiovascular diseases. Among them, RvD1 and LXA4 prevent atrial fibrillation (AF) remodeling in the atria and cardiac hypertrophy, respectively in animal models. However, little is known about their electrophysiological effects on cardiac voltage-gated (VG) ion channels. Methods and resultsWe used the patch-clamp technique in heterologous systems and cardiomyocytes to assess the acute effect of RvD1, and LXA4, on VG potassium currents. In silico simulations were used to predict the effect of current modulation on the atrial and ventricular action potentials (AP). RvD1 and LXA4 reduced IKs (channel KV7.1/KCNE1) in COS-7 cells and guinea-pig cardiomyocytes without modifying its voltage dependence; RvD1 was more potent than LXA4. In heterologous systems, RvD1 was also tested on IKur (channel KV1.5), Ito (channel KV4.3/KChIP2), IKr (channel KV11.1), and IK1 (channel Kir2.1) with the largest inhibitory effect on IKs and IKr. In simulations RvD1 prolonged repolarization significantly in both atrial and ventricular myocytes. ConclusionThe results provide a comprehensive evaluation of RvD1 and LXA4 on cardiac human potassium channels, at pathophysiological relevant concentrations, being RvD1 more potent than LXA4. The predicted effects on the action potential suggest that, along with their antiinflammatory action, RvD1 may reverse AF-induced electrical remodeling in the atria by direct modulation of K+ currents. The same action might instead contribute to ventricular functional remodeling; however, direct evidence for this is missing.

pharmacology and toxicology↗

bioRxiv2024

Lipophilic compounds restore wt function of neurodevelopmental-associated KCNQ3 mutations.

A major driver of neuronal hyperexcitability is dysfunction of K+ channels, including voltage-gated KCNQ2/3 channels. Their slow activation and deactivation kinetics produces a current that regulates membrane potential and impedes repetitive firing. Mutations in KCNQ2 and KCNQ3 lead to a wide spectrum of neurodevelopmental disorders (NDDs), ranging from benign familial neonatal seizures to severe epileptic encephalopathies and autism spectrum disorders. However, the impact of these mutations on KCNQ channel function remains poorly understood and existing treatments have unpleasant side effects. Here we use voltage clamp fluorometry and molecular dynamic simulations to investigate how R227Q and R236C, two novel NDD-causing mutations in the voltage sensor of KCNQ3, impair channel function. We show that the two mutations perturb channel gating by two distinct mechanisms: R227Q altering voltage sensor movement and R236C altering voltage sensor-to-gate coupling. Our study further shows that polyunsaturated fatty acids (PUFAs), a novel class of ion channel modulators, primarily target the voltage sensor domain in its activated conformation and yield partial and complete restoration of wt function in R227Q- and R236C-containing channels, respectively. Our results reveal the potential of PUFAs to be developed into therapies for diverse KCNQ3-based channelopathies.

biophysics↗