Biology subjects

DEVAL, E.

Publications and source records attributed to DEVAL, E..

3 recordsLinked to original sources

bioRxiv2025

Short RFamide and CFamide peptides as novel positive modulators of Acid-Sensing Ion Channel 3 with similar potentiating effects but different reversibility

Acid-sensing ion channels (ASICs) are members of the DEG/ENaC family that includes the only known peptide-gated ion channels. While ASICs are gated by protons, they have kept sensitivity to peptides and are notably modulated by the molluscan FMRFamide and other related mammalian neuropeptides ending by the RFamide motif. Screening efforts have been made to identify and characterize natural peptides able to modulate ASICs activity, and some peptides from different species are already known to modulate ASIC1a, ASIC1b and ASIC3. We identified here a set of synthetic short amidated hexapeptides, initially designed thirty years ago for their ability to inhibit the Na/Ca exchanger, as potent and selective positive modulators of the ASIC3 acid-induced activity. We focused on two of them, a RFamide peptide (FRCCRFamide) and a CFamide peptide (FR[C][R][C]Famide), demonstrating that they have similar specificity for and effects on ASIC3. The potentiating effects of the two peptides are due to a strong slow-down of the current desensitization, leading to an increase in the amount of current induced by acid pH ([≤]pH6.6), with apparent affinities ranging from 1 to 5 {micro}M. Surprisingly, the washout kinetic for the FR[C][C]RFamide peptide was much slower than those of FR[C][R][C]Famide and other known RFamide peptides, suggesting potential differences in their mechanisms of action. Computational modeling and structure-function analysis reveal interactions of both peptides with the non-proton binding site of ASIC3 initially identified for the synthetic compound GMQ (2-guanidine-4-methylquinazoline), as already reported before for other RFamide peptides, but our data also suggest possible additional effects of FR[C][C]RFamide involving directly or indirectly the proton binding domain. These findings expand our understanding of peptide modulation of ASIC channels and identify novel pharmacological tools selective among ASICs for investigating ASIC3 function.

pharmacology and toxicology↗

bioRxiv2021

Lysophosphatidylcholine induces heat pain hypersensitivity in obese mice fed with a high-fat diet through activation of peripheral Acid-Sensing Ion Channel 3

Diet induced obesity is one of the major causes of obesity, which affects 13% of the worlds adult population. Obesity is correlated to chronic pain regardless of other components of the metabolic syndrome. Our study focuses on investigating the effect of high-fat diet induced obesity on peripheral sensory neurons activity and pain perception, followed by deciphering the underlying cellular and molecular mechanisms that involve Acid-Sensing Ion Channel 3 (ASIC3). We show here that heat sensitive C-fibers from mice made obese by consumption of a high-fat diet exhibited an increased activity during baseline and upon heating. Obese mice showed long-lasting heat pain hypersensitivity once obesity was well established, while mechanical sensitivity was not affected. We found that the serum of obese mice was enriched in lysophosphatidylcholine (LPC) species (LPC16:0, LPC18:0 and LPC18:1), which activate ASIC3 channels and increased peripheral neuron excitability. Genetic deletion and in vivo pharmacological inhibition of ASIC3 protected and rescued mice from obesity-induced thermal hypersensitivity. Our results identify ASIC3 channels in DRG neurons and circulating LPC species that activate them as a mechanism contributing to heat pain hypersensitivity associated with high-fat diet induced obesity.

neuroscience↗

bioRxiv2021

Involvement of ASIC1a channels in the spinal processing of pain information by deep projection neurons

Dorsal horn of the spinal cord is an important crossroad of pain neuraxis, especially for the neuronal plasticity mechanisms that can lead to chronic pain states. Windup is a well-known spinal pain facilitation process initially described several decades ago, but which exact mechanism is still not fully understood. Here, we combine both ex vivo and in vivo electrophysiological recordings of spinal neurons with computational modelling to demonstrate a role for ASIC1a-containing channels in the windup process. Spinal application of the ASIC1a inhibitory venom peptides mambalgin-1 and psalmotoxin-1 (PcTx1) significantly reduces the ability of deep wide dynamic range (WDR) neurons to develop windup in vivo. All deep WDR-like neurons recorded from spinal slices exhibit an ASIC current with biophysical and pharmacological characteristics consistent with functional expression of ASIC1a/ASIC2 heteromeric channels. A computational model of WDR neuron supplemented with heteromeric ASIC1a/ASIC2 channel parameters accurately reproduces the experimental data, further supporting a positive contribution of these channels to windup. It also predicts a calcium-dependent windup decrease for elevated ASIC conductances, a phenomenon that was experimentally validated using either a combination of calcium-activated potassium channel inhibitory peptides (apamin and iberiotoxin), or the Texas coral snake ASIC-activating toxin (MitTx). This study demonstrates a possible dual contribution to windup of calcium permeable ASIC1a/ASIC2 channels in deep laminae projecting neurons, promoting it upon moderate channel activity, but ultimately leading to calcium-dependent windup inhibition associated to potassium channels when activity increases.

neuroscience↗