Lycocasine A, a Lycopodium Alkaloid from Lycopodiastrum casuarinoides and Its Acid-Sensing Ion Channel 1a Inhibitory Activity.

A novel Lycopodium alkaloid, lycocasine A (1), and seven known Lycopodium alkaloids (2-8), were isolated from Lycopodiastrum casuarinoides. Their structures were determined through NMR, HRESIMS, and X-ray diffraction analysis. Compound 1 features an unprecedented 5/6/6 tricyclic skeleton, highlighted by a 5-aza-tricyclic[6,3,1,02,6]dodecane motif. In bioactivity assays, compound 1 demonstrated weak inhibitory activity against acid-sensing ion channel 1a.

4-(Azolyl)-Benzamidines as a Novel Chemotype for ASIC1a Inhibitors.

Acid-sensing ion channels (ASICs) play a key role in the perception and response to extracellular acidification changes. These proton-gated cation channels are critical for neuronal functions, like learning and memory, fear, mechanosensation and internal adjustments like synaptic plasticity. Moreover, they play a key role in neuronal degeneration, ischemic neuronal injury, seizure termination, pain-sensing, etc. Functional ASICs are homo or heterotrimers formed with (ASIC1-ASIC3) homologous subunits. ASIC1a, a major ASIC isoform in the central nervous system (CNS), possesses an acidic pocket in the extracellular region, which is a key regulator of channel gating. Growing data suggest that ASIC1a channels are a potential therapeutic target for treating a variety of neurological disorders, including stroke, epilepsy and pain. Many studies were aimed at identifying allosteric modulators of ASIC channels. However, the regulation of ASICs remains poorly understood. Using all available crystal structures, which correspond to different functional states of ASIC1, and a molecular dynamics simulation (MD) protocol, we analyzed the process of channel inactivation. Then we applied a molecular docking procedure to predict the protein conformation suitable for the amiloride binding. To confirm the effect of its sole active blocker against the ASIC1 state transition route we studied the complex with another MD simulation run. Further experiments evaluated various compounds in the Enamine library that emerge with a detectable ASIC inhibitory activity. We performed a detailed analysis of the structural basis of ASIC1a inhibition by amiloride, using a combination of in silico approaches to visualize its interaction with the ion pore in the open state. An artificial activation (otherwise, expansion of the central pore) causes a complex modification of the channel structure, namely its transmembrane domain. The output protein conformations were used as a set of docking models, suitable for a high-throughput virtual screening of the Enamine chemical library. The outcome of the virtual screening was confirmed by electrophysiological assays with the best results shown for three hit compounds.

pHeeling the pHorce.

In this issue of Neuron, Yamada et al.1 show that fast excitatory neurotransmission by protons acting at acid-sensing ion channels (ASICs) mediates mechanical force-evoked signaling at the Merkel cell-neurite complex, contributing to mammalian tactile discrimination.

Complex alterations in inflammatory pain and analgesic sensitivity in young and ageing female rats: involvement of ASIC3 and Nav1.8 in primary sensory neurons.

OBJECTIVE AND DESIGN: Our aim was to determine an age-dependent role of Nav1.8 and ASIC3 in dorsal root ganglion (DRG) neurons in a rat pre-clinical model of long-term inflammatory pain. METHODS: We compared 6 and 24 months-old female Wistar rats after cutaneous inflammation. We used behavioral pain assessments over time, qPCR, quantitative immunohistochemistry, selective pharmacological manipulation, ELISA and in vitro treatment with cytokines. RESULTS: Older rats exhibited delayed recovery from mechanical allodynia and earlier onset of spontaneous pain than younger rats after inflammation. Moreover, the expression patterns of Nav1.8 and ASIC3 were time and age-dependent and ASIC3 levels remained elevated only in aged rats. In vivo, selective blockade of Nav1.8 with A803467 or of ASIC3 with APETx2 alleviated mechanical and cold allodynia and also spontaneous pain in both age groups with slightly different potency. Furthermore, in vitro IL-1ß up-regulated Nav1.8 expression in DRG neurons cultured from young but not old rats. We also found that while TNF-α up-regulated ASIC3 expression in both age groups, IL-6 and IL-1ß had this effect only on young and aged neurons, respectively. CONCLUSION: Inflammation-associated mechanical allodynia and spontaneous pain in the elderly can be more effectively treated by inhibiting ASIC3 than Nav1.8.

Paradoxical potentiation of the exercise pressor reflex by endomorphin 2 in the presence of naloxone.

When contracting muscles are freely perfused, the acid-sensing ion channel 3 (ASIC3) on group IV afferents plays a minor role in evoking the exercise pressor reflex. We recently showed in isolated dorsal root ganglion neurons innervating the gastrocnemius muscles that two mu opioid receptor agonists, namely endomorphin 2 and oxycodone, potentiated the sustained inward ASIC3 current evoked by acidic solutions. This in vitro finding prompted us to determine whether endomorphin 2 and oxycodone, when infused into the arterial supply of freely perfused contracting hindlimb muscles, potentiated the exercise pressor reflex. We found that infusion of endomorphin 2 and naloxone in decerebrated rats potentiated the pressor responses to contraction of the triceps surae muscles. The endomorphin 2-induced potentiation of the pressor responses to contraction was prevented by infusion of APETx2, an ASIC3 antagonist. Specifically, the peak pressor response to contraction averaged 19.3 ± 5.6 mmHg for control (n = 10), 27.2 ± 8.1 mmHg after naloxone and endomorphin 2 infusion (n = 10), and 20 ± 8 mmHg after APETx2 and endomorphin 2 infusion (n = 10). Infusion of endomorphin 2 and naloxone did not potentiate the pressor responses to contraction in ASIC3 knockout rats (n = 6). Partly similar findings were observed when oxycodone was substituted for endomorphin 2. Oxycodone infusion significantly increased the exercise pressor reflex over its control level, but subsequent APETx2 infusion failed to restore the increase to its control level (n = 9). The peak pressor response averaged 23.1 ± 8.6 mmHg for control (n = 9), 33.2 ± 11 mmHg after naloxone and oxycodone were infused (n = 9), and 27 ± 8.6 mmHg after APETx2 and oxycodone were infused (n = 9). Our data suggest that after opioid receptor blockade, ASIC3 stimulation by the endogenous mu opioid, endomorphin 2, potentiated the exercise pressor reflex.NEW & NOTEWORTHY This paper provides the first in vivo evidence that endomorphin 2, an endogenous opioid peptide, can paradoxically increase the magnitude of the exercise pressor reflex by an ASIC3-dependent mechanism even when the contracting muscles are freely perfused.

NGF contributes to activities of acid-sensing ion channels in dorsal root ganglion neurons of male rats with experimental peripheral artery disease.

A feature of peripheral artery diseases (PAD) includes limb ischemia/reperfusion (I/R) and ischemia. Both I/R and ischemia amplify muscle afferent nerve-activated reflex sympathetic nervous and blood pressure responses (termed as exercise pressor reflex). Nevertheless, the underlying mechanisms responsible for the exaggerated autonomic responses in PAD are undetermined. Previous studies suggest that acid-sensing ion channels (ASICs) in muscle dorsal root ganglion (DRG) play a leading role in regulating the exercise pressor reflex in PAD. Thus, we determined if signaling pathways of nerve growth factor (NGF) contribute to the activities of ASICs in muscle DRG neurons of PAD. In particular, we examined ASIC1a and ASIC3 currents in isolectin B4 -negative muscle DRG neurons, a distinct subpopulation depending on NGF for survival. Hindlimb I/R and ischemia were obtained in male rats. In results, femoral artery occlusion increased the levels of NGF and NGF-stimulated TrkA receptor in DRGs, whereas they led to upregulation of ASIC3 but not ASIC1a. In addition, application of NGF onto DRG neurons increased the density of ASIC3 currents and the effect of NGF was significantly attenuated by TrkA antagonist GW441756. Moreover, the enhancing effect of NGF on the density of ASIC3-like currents was decreased by the respective inhibition of intracellular signaling pathways, namely JNK and NF-κB, by antagonists SP600125 and PDTC. Our results suggest contribution of NGF to the activities of ASIC3 currents via JNK and NF-κB signaling pathways in association with the exercise pressor reflex in experimental PAD.

Inhibiting acid-sensing ion channel exerts neuroprotective effects in experimental epilepsy via suppressing ferroptosis.

BACKGROUND: Epilepsy is a chronic neurological disease characterized by repeated and unprovoked epileptic seizures. Developing disease-modifying therapies (DMTs) has become important in epilepsy studies. Notably, focusing on iron metabolism and ferroptosis might be a strategy of DMTs for epilepsy. Blocking the acid-sensing ion channel 1a (ASIC1a) has been reported to protect the brain from ischemic injury by reducing the toxicity of [Ca2+ ]i . However, whether inhibiting ASIC1a could exert neuroprotective effects and become a novel target for DMTs, such as rescuing the ferroptosis following epilepsy, remains unknown. METHODS: In our study, we explored the changes in ferroptosis-related indices, including glutathione peroxidase (GPx) enzyme activity and levels of glutathione (GSH), iron accumulation, lipid degradation products-malonaldehyde (MDA) and 4-hydroxynonenal (4-HNE) by collecting peripheral blood samples from adult patients with epilepsy. Meanwhile, we observed alterations in ASIC1a protein expression and mitochondrial microstructure in the epileptogenic foci of patients with drug-resistant epilepsy. Next, we accessed the expression and function changes of ASIC1a and measured the ferroptosis-related indices in the in vitro 0-Mg2+ model of epilepsy with primary cultured neurons. Subsequently, we examined whether blocking ASIC1a could play a neuroprotective role by inhibiting ferroptosis in epileptic neurons. RESULTS: Our study first reported significant changes in ferroptosis-related indices, including reduced GPx enzyme activity, decreased levels of GSH, iron accumulation, elevated MDA and 4-HNE, and representative mitochondrial crinkling in adult patients with epilepsy, especially in epileptogenic foci. Furthermore, we found that inhibiting ASIC1a could produce an inhibitory effect similar to ferroptosis inhibitor Fer-1, alleviate oxidative stress response, and decrease [Ca2+ ]i overload by inhibiting the overexpressed ASIC1a in the in vitro epilepsy model induced by 0-Mg2+ . CONCLUSION: Inhibiting ASIC1a has potent neuroprotective effects via alleviating [Ca2+ ]i overload and regulating ferroptosis on the models of epilepsy and may act as a promising intervention in DMTs.

ASICs mediate fast excitatory synaptic transmission for tactile discrimination.

Tactile discrimination, the ability to differentiate objects' physical properties such as texture, shape, and edges, is essential for environmental exploration, social interaction, and early childhood development. This ability heavily relies on Merkel cell-neurite complexes (MNCs), the tactile end-organs enriched in the fingertips of humans and the whisker hair follicles of non-primate mammals. Although recent studies have advanced our knowledge on mechanical transduction in MNCs, it remains unknown how tactile signals are encoded at MNCs. Here, using rodent whisker hair follicles, we show that tactile signals are encoded at MNCs as fast excitatory synaptic transmission. This synaptic transmission is mediated by acid-sensing ion channels (ASICs) located on the neurites of MNCs, with protons as the principal transmitters. Pharmacological inhibition or genetic deletion of ASICs diminishes the tactile encoding at MNCs and impairs tactile discrimination in animals. Together, ASICs are required for tactile encoding at MNCs to enable tactile discrimination in mammals.

Opioid Analgesic as a Positive Allosteric Modulator of Acid-Sensing Ion Channels.

Tafalgin (Taf) is a tetrapeptide opioid used in clinical practice in Russia as an analgesic drug for subcutaneous administration as a solution (4 mg/mL; concentration of 9 mM). We found that the acid-sensing ion channels (ASICs) are another molecular target for this molecule. ASICs are proton-gated sodium channels that mediate nociception in the peripheral nervous system and contribute to fear and learning in the central nervous system. Using electrophysiological methods, we demonstrated that Taf could increase the integral current through heterologically expressed ASIC with half-maximal effective concentration values of 0.09 mM and 0.3 mM for rat and human ASIC3, respectively, and 1 mM for ASIC1a. The molecular mechanism of Taf action was shown to be binding to the channel in the resting state and slowing down the rate of desensitization. Taf did not compete for binding sites with both protons and ASIC3 antagonists, such as APETx2 and amiloride (Ami). Moreover, Taf and Ami together caused an unusual synergistic effect, which was manifested itself as the development of a pronounced second desensitizing component. Thus, the ability of Taf to act as a positive allosteric modulator of these channels could potentially cause promiscuous effects in clinical practice. This fact must be considered in patients' treatment.

Progress on functions of intracellular domain of trimeric ligand-gated ion channels. / ä¸‰èšä½“é ä½“é—¨æŽ§ç¦»å­é€šé“èƒžå† åŒºåŸŸçš„åŠŸèƒ½ç ”ç©¶è¿›å±•.

Ligand-gated ion channels are a large category of essential ion channels, modulating their state by binding to specific ligands to allow ions to pass through the cell membrane. Purinergic ligand-gated ion channel receptors (P2XRs) and acid-sensitive ion channels (ASICs) are representative members of trimeric ligand-gated ion channel. Recent studies have shown that structural differences in the intracellular domain of P2XRs may determine the desensitization process. The lateral fenestrations of P2XRs potentially serve as a pathway for ion conductance and play a decisive role in ion selectivity. Phosphorylation of numerous amino acid residues in the P2XRs are involved in regulating the activity of ion channels. Additionally, the P2XRs interact with other ligand-gated ion channels including N-methyl-D-aspartate receptors, γ-aminobutyric acid receptors, 5-hydroxytryptamin receptors and nicotinic acetylcholine receptors, mediating physiological processes such as synaptic plasticity. Conformational changes in the intracellular domain of the ASICs expose binding sites of intracellular signal partners, facilitating metabolic signal transduction. Amino acids such as Val16, Ser17, Ile18, Gln19 and Ala20 in the ASICs participate in channel opening and membrane expression. ASICs can also bind to intracellular proteins, such as CIPP and p11, to regulate channel function. Many phosphorylation sites at the C-terminus and N-terminus of ASICs are involved in the regulation of receptors. Furthermore, ASICs are involved in various physiological and pathophysiological processes, which include pain, ischemic stroke, psychiatric disorders, and neurodegenerative disease. In this article, we review the roles of the intracellular domains of these trimeric ligand-gated ion channels in channel gating as well as their physiological and pathological functions, in order to provide new insights into the discovery of related drugs.

Molecular determinants of ASIC1 modulation by divalent cations.

Acid-sensing ion channels (ASICs) are proton-gated cation channels widely expressed in the nervous system. ASIC gating is modulated by divalent cations as well as small molecules; however, the molecular determinants of gating modulation by divalent cations are not well understood. Previously, we identified two small molecules that bind to ASIC1a at a novel site in the acidic pocket and modulate ASIC1 gating in a manner broadly resembling divalent cations, raising the possibility that these small molecules may help to illuminate the molecular determinants of gating modulation by divalent cations. Here, we examined how these two groups of modulators might interact as well as mutational effects on ASIC1a gating and its modulation by divalent cations. Our results indicate that binding of divalent cations to an acidic pocket site plays a key role in gating modulation of the channel.

Inhibition of ASIC1a Improves Behavioral Recovery after Stroke.

Stroke continues to be a leading cause of death and long-term disabilities worldwide, despite extensive research efforts. The failure of multiple clinical trials raises the need for continued study of brain injury mechanisms and novel therapeutic strategies for ischemic stroke. The contribution of acid-sensing ion channel 1a (ASIC1a) to neuronal injury during the acute phase of stroke has been well studied; however, the long-term impact of ASIC1a inhibition on stroke recovery has not been established. The present study sought to bridge part of the translational gap by focusing on long-term behavioral recovery after a 30 min stroke in mice that had ASIC1a knocked out or inhibited by PcTX1. The neurological consequences of stroke in mice were evaluated before and after the stroke using neurological deficit score, open field, and corner turn test over a 28 d period. ASIC1a knock-out and inhibited mice showed improved neurological scores more quickly than wild-type control and vehicle-injected mice after the stroke. ASIC1a knock-out mice also recovered from mobility deficits in the open field test more quickly than wild-type mice, while PcTX1-injected mice did not experience significant mobility deficits at all after the stroke. In contrast to vehicle-injected mice that showed clear-sidedness bias in the corner turn test after stroke, PcTX1-injected mice never experienced significant-sidedness bias at all. This study supports and extends previous work demonstrating ASIC1a as a potential therapeutic target for the treatment of ischemic stroke.

ASIC3 roles in mechanosensitive elongation of nucleus pulposus cells.

Morphological changes of the nucleus pulposus (NP) cells occur concomitantly as part of the intervertebral disc (IVD) degeneration and excessive mechanical loading has been speculated as a significant key factor for contributing to such morphological changes. Therefore, we hypothesize that stress exerted on NP cells can cause a deformity of nucleus in response. The changes of cell morphology is observed in degenerative nucleus pulposus. One of the reasons for degeneration of NP is due to overloading of NP especially in the obese population. So the nucleus deformity caused by stress/force is of our study interest. To delineate the effects and role of mechanical stress, we developed a 3D assay using hydrogel cultures with a circular hole generated with needle indentation to simulate a local stress concentration along the edge of the hole. A stressed zone, encompassing 100 µm of range from the circular edge, is defined based on stress concentration calculation to enable quantitative analysis against the control zone. Our results demonstrated that the circular hole produces stress-induced morphological changes in NP cells. The tangential elongation of NP cells and their nucleus shape changes in the stressed zone are significantly increased compared to the non-stressed control zone. It is proposed that the cell elongation is a direct response to elevated stress within the stressed zone. Subsequently we found the stress induced morphological changes of the NP cells can be significantly reduced by inhibiting ASIC3. This suggests ASIC3 plays an important role of play in mechano-signaling of NP cells.

Acid-sensing ion channels and downstream signalling in cancer cells: is there a mechanistic link?

It is increasingly appreciated that the acidic microenvironment of a tumour contributes to its evolution and clinical outcomes. However, our understanding of the mechanisms by which tumour cells detect acidosis and the signalling cascades that it induces is still limited. Acid-sensing ion channels (ASICs) are sensitive receptors for protons; therefore, they are also candidates for proton sensors in tumour cells. Although in non-transformed tissue, their expression is mainly restricted to neurons, an increasing number of studies have reported ectopic expression of ASICs not only in brain cancer but also in different carcinomas, such as breast and pancreatic cancer. However, because ASICs are best known as desensitizing ionotropic receptors that mediate rapid but transient signalling, how they trigger intracellular signalling cascades is not well understood. In this review, we introduce the acidic microenvironment of tumours and the functional properties of ASICs, point out some conceptual problems, summarize reported roles of ASICs in different cancers, and highlight open questions on the mechanisms of their action in cancer cells. Finally, we propose guidelines to keep ASIC research in cancer on solid ground.

The mechanosensitive ion channel ASIC2 mediates both proprioceptive sensing and spinal alignment.

By translating mechanical forces into molecular signals, proprioceptive neurons provide the CNS with information on muscle length and tension, which is necessary to control posture and movement. However, the identities of the molecular players that mediate proprioceptive sensing are largely unknown. Here, we confirm the expression of the mechanosensitive ion channel ASIC2 in proprioceptive sensory neurons. By combining in vivo proprioception-related functional tests with ex vivo electrophysiological analyses of muscle spindles, we showed that mice lacking Asic2 display impairments in muscle spindle responses to stretch and motor coordination tasks. Finally, analysis of skeletons of Asic2 loss-of-function mice revealed a specific effect on spinal alignment. Overall, we identify ASIC2 as a key component in proprioceptive sensing and a regulator of spine alignment.

Genetic exploration of roles of acid-sensing ion channel subtypes in neurosensory mechanotransduction including proprioception.

Although acid-sensing ion channels (ASICs) are proton-gated ion channels responsible for sensing tissue acidosis, accumulating evidence has shown that ASICs are also involved in neurosensory mechanotransduction. However, in contrast to Piezo ion channels, evidence of ASICs as mechanically gated ion channels has not been found using conventional mechanoclamp approaches. Instead, ASICs are involved in the tether model of mechanotransduction, with the channels gated via tethering elements of extracellular matrix and intracellular cytoskeletons. Methods using substrate deformation-driven neurite stretch and micropipette-guided ultrasound were developed to reveal the roles of ASIC3 and ASIC1a, respectively. Here we summarize the evidence supporting the roles of ASICs in neurosensory mechanotransduction in knockout mouse models of ASIC subtypes and provide insight to further probe their roles in proprioception.

The role of acid-sensing ion channels in monosodium urate-induced gouty pain in mice.

Acid-sensing ion channels (ASICs) in dorsal root ganglion (DRG) neurons play an important role in inflammatory pain. The objective of this study is to observe the regulatory role of ASICs in monosodium urate (MSU) crystal-induced gout pain and explore the basis for ASICs in DRG neurons as a target for gout pain treatment. The gout arthritis model was induced by injecting MSU crystals into the ankle joint of mice. The circumference of the ankle joint was used to evaluate the degree of swelling; the von Frey filaments were used to determine the withdrawal threshold of the paw. ASIC currents and action potentials (APs) were recorded by patch clamp technique in DRG neurons. The results displayed that injecting MSU crystals caused ankle edema and mechanical hyperalgesia of the paw, which was relieved after amiloride treatment. The ASIC currents in DRG neurons were increased to a peak on the second day after injecting MSU crystals, which were decreased after amiloride treatment. MSU treatment increased the current density of ASICs in different diameter DRG cells. MSU treatment does not change the characteristics of AP. The results suggest that ASICs in DRG neurons participate in MSU crystal-induced gout pain.

Acid-sensing ion channel 3 mediates pain hypersensitivity associated with high-fat diet consumption in mice.

ABSTRACT: Lipid-rich diet is the major cause of obesity, affecting 13% of the worldwide adult population. Obesity is a major risk factor for metabolic syndrome that includes hyperlipidemia and diabetes mellitus. The early phases of metabolic syndrome are often associated with hyperexcitability of peripheral small diameter sensory fibers and painful diabetic neuropathy. Here, we investigated the effect of high-fat diet-induced obesity on the activity of dorsal root ganglion (DRG) sensory neurons and pain perception. We deciphered the underlying cellular mechanisms involving the acid-sensing ion channel 3 (ASIC3). We show that mice made obese through consuming high-fat diet developed the metabolic syndrome and prediabetes that was associated with heat pain hypersensitivity, whereas mechanical sensitivity was not affected. Concurrently, the slow conducting C fibers in the skin of obese mice showed increased activity on heating, whereas their mechanosensitivity was not altered. Although ASIC3 knockout mice fed with high-fat diet became obese, and showed signs of metabolic syndrome and prediabetes, genetic deletion, and in vivo pharmacological inhibition of ASIC3, protected mice from obesity-induced thermal hypersensitivity. We then deciphered the mechanisms involved in the heat hypersensitivity of mice and found that serum from high-fat diet-fed mice was enriched in lysophosphatidylcholine (LPC16:0, LPC18:0, and LPC18:1). These enriched lipid species directly increased the activity of DRG neurons through activating the lipid sensitive ASIC3 channel. Our results identify ASIC3 channel in DRG neurons and circulating lipid species as a mechanism contributing to the hyperexcitability of nociceptive neurons that can cause pain associated with lipid-rich diet consumption and obesity.

Role of proprioceptors in chronic musculoskeletal pain.

Proprioceptors are non-nociceptive low-threshold mechanoreceptors. However, recent studies have shown that proprioceptors are acid-sensitive and express a variety of proton-sensing ion channels and receptors. Accordingly, although proprioceptors are commonly known as mechanosensing neurons that monitor muscle contraction status and body position, they may have a role in the development of pain associated with tissue acidosis. In clinical practice, proprioception training is beneficial for pain relief. Here we summarize the current evidence to sketch a different role of proprioceptors in 'non-nociceptive pain' with a focus on their acid-sensing properties.

Redistribution of ASIC1a channels triggered by IL-6: Potential role of ASIC1a in neuroinflammation.

Cytokines, particularly IL-6, play a crucial role in modulating immune responses in the central nervous system (CNS). Elevated IL-6 levels have been observed in neuroinflammatory conditions, as well as in the sera and brains of patients with neurodegenerative diseases such as Parkinson's, Huntington's, Multiple Sclerosis, and Alzheimer's. Additionally, alterations in regional brain pH have been noted in these conditions. Acid-sensing ion channels (ASICs), including ASIC1a, activated by low pH levels, are highly abundant in the CNS and have recently been associated with various neurological disorders. Our study examined the impact of IL-6 on ASIC1a channels in cell cultures, demonstrating IL-6-induced the redistribution of cytosolic ASIC1a channels to the cell membrane. This redistribution was accompanied by increased ASIC1a current amplitude upon activation, as well as elevated levels of phosphorylated CaMKII and ERK kinases. Additionally, we observed posttranslational modifications on the ASIC1a channel itself. These findings provide insight into a potential link between inflammatory processes and neurodegenerative mechanisms, highlighting ASIC1a channels as promising therapeutic targets in these conditions.