The maintenance of cytosolic pH in its physiological range is required for normal neuronal activity, and even minor alterations can have serious consequences. Under normal physiological conditions, intra- and extracellular pH is maintained between 7.0 and 7.3; however, normal neuronal activity causes local pH changes (Chen and Chesler, 1992; Chesler and Kaila, 1992; Makani and Chesler, 2007; Magnotta et al., 2012). In the mammalian central nervous system (CNS), increased neuronal activity and the intense synchronous synaptic activity occurring in the synaptic plasticity process alter pH, producing alkalinization followed by acidification (DeVries, 2001; Du et al., 2014).

Under pathological conditions, including ischemic strokes, seizures, and inflammation associated with several neurodegenerative diseases, the pH shifts toward a persistent acidification that is correlated with neuronal hyperexcitability (Chiacchiaretta et al., 2017).

Neuroinflammation within the brain or spinal cord is mediated by the release of cytokines, chemokines, reactive oxygen species produced from resident microglia and astrocytes, endothelial cells, and peripherally derived immune cells (DiSabato et al., 2016). In the last decades, correlation between neuroinflammation and neurodegeneration has become increasingly solid in the light of accumulating evidence gathered on Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS) (Salter and Stevens, 2017).

Several studies in animal models and in humans have demonstrated that neurodegenerative diseases, characterized by a persistent inflammatory state, are associated with a significant reduction in the brain pH (Amor et al., 2010; Tyrtyshnaia et al., 2016; Decker et al., 2021), suggesting that neuroinflammation per se affects brain pH level. All this evidence has prompted the investigation of the role of acid-sensing ion channels (ASICs) in neurodegenerative diseases. The present work provides an overview of the possible roles of ASIC1a in neurodegenerative conditions and highlights this protein as a new potential therapeutic target.

ASICs belong to a class of voltage-insensitive cation channels, which are widely expressed in the central and peripheral nervous systems (Sherwood et al., 2012; Vullo and Kellenberger, 2020; Rook et al., 2021). Today, it is well accepted that protons (H⁺) can act as neurotransmitters through the specific activation of proton-sensing channels, and these channels were cloned and named for the first time as ASICs in 1997 (Waldmann et al., 1997). Thereafter, many studies have investigated their structure, expression, and localization, and many experimental ligands, to explore and understand the role and function of ASIC in physiological and pathological processes, were developed (Figure 1; Chesler, 2003; Mango and Nisticò, 2020; Rook et al., 2021). Among six different mammalian protein subunits that have been cloned (ASIC1a, ASIC1b, ASIC2a, ASIC2b, ASIC3, and ASIC4), ASIC1 and ASIC2 are predominant subunits in the CNS (Waldmann et al., 1997; Chen et al., 1998; Bässler et al., 2001). Each ASIC subunit has two transmembrane domains and a large extracellular domain enriched with acidic residues. ASICs can be assembled as either homotrimers or heterotrimers to form functional channels (Bassilana et al., 1997; Babinski et al., 1999; Jasti et al., 2007; Gonzales et al., 2009; Magnotta et al., 2012; Rook et al., 2021).

The most important characteristic of ASICs is the high pH sensitivity (Wemmie et al., 2013) making them the best candidates for pH sentinels in the brain that can detect and respond to small pH variations (Papalampropoulou-Tsiridou et al., 2020; Rook et al., 2021). A recent study has provided insights into the role of ASIC currents in the generation of action potential (AP) firing in neurons in relation to the speed of pH change. The authors demonstrate that moderate acidification (4–10 s) mediates AP increase, while slow acidification (>10 s) is not able to induce AP changes, suggesting a new important parameter that influences ASIC modulation of neuronal depolarization (Alijevic et al., 2020).

Most studies are focused on the most abundant form of an ASIC channel expressed in the CNS, which is represented by ASIC1a. Activation of ASIC1a plays a key role in pathological processes by promoting neuronal death via calcium (Ca²⁺)-mediated toxicity (Yermolaieva et al., 2004). The abundant expression of ASIC1a in discrete regions of the brain, such as the hippocampus, cortex, striatum, and amygdala (Alvarez de la Rosa et al., 2003; Wemmie et al., 2003; Coryell et al., 2009) and the characteristic to be Ca²⁺ permeable has suggested a role for this channel in calcium-related processes such as synaptic plasticity, learning and memory, as well as neuronal death (Wemmie et al., 2002; Gao et al., 2015; Wang et al., 2015). Accordingly, blocking ASIC1a affects multiple forms of synaptic plasticity in many brain regions including the amygdala and hippocampus (Wemmie et al., 2002, 2003; Du et al., 2014; Mango et al., 2017; Mango and Nisticò, 2020). Inhibition of ASIC1a produces a reduction in magnitude of both forms of synaptic plasticity long-term potentiation (LTP) and long-term depression (LTD) and ASIC1a KO mice show impairment of learning and memory evaluated with the Morris water maze and elevated-plus maze behavioral tests.

Moreover, the interplay between ASIC1a and NMDA, AMPA, and GABA receptors represents a potential target for acidotoxicity and exitotoxicity that occur in pathological conditions, such as ischemia (Gao et al., 2005, 2016; Chen et al., 2011; González-Inchauspe et al., 2017). Intriguingly, protons are able to modulate different synaptic receptors including AMPA and NMDA glutamate receptors (Tang et al., 1990; Traynelis and Cull-Candy, 1990; Lei et al., 2001), as well as GABAA receptors (Kaila, 1994; Dietrich and Morad, 2010), indicating that pH changes affect neuronal excitability, neurotransmission, and post-synaptic responses (Chen and Chesler, 1992; Makani and Chesler, 2007; Dietrich and Morad, 2010).

Growing evidence supports the relationship between neuroinflammation and synaptic degeneration as a common feature in neurodegenerative diseases including AD, PD, and MS (Nisticò et al., 2017; Guzman-Martinez et al., 2019). Acidosis and accumulation of protons in the extracellular space represent hallmarks of the inflammatory process (see Diaz et al., 2018). The shift to the acidic pH was observed in normal aging and in patients affected by a variety of neurodegenerative disorders and was also confirmed in experimental models of neuroinflammation (Roberts and Sick, 1996; Roberts and Chih, 1997; Friese et al., 2007; Vergo et al., 2011; Mandal et al., 2012; Tyrtyshnaia et al., 2016).

To date, there is limited experimental evidence linking ASICs to neuroinflammation. For example, NSAIDs were reported to act against ASICs by both preventing inflammation-induced increase in expression and directly inhibiting the channels (Voilley et al., 2001). Our group has published that CHF5074 (also called CSP-1103), a flurbiprofen derivative, induces inhibition of ASIC1a-mediated currents elicited by application of pH 5.5 bath medium (IC50 ∼50 nM) (Mango et al., 2014). A previous work has also demonstrated an increased expression of ASIC3 on nerve afferents supplying joints in response to inflammatory stimulus and an anti-inflammatory action exerted by ASIC3 inhibitors in animal models of rheumatoid arthritis. Notably, ASIC^–/– animals manifest higher joint inflammation and destruction compared with ASIC^+/+ controls (Sluka et al., 2013).

Therefore, ASICs represent the receptors on which the protons act as neurotransmitter and prolonged changes in pH shift likely contribute to the chronic inflammatory states underlying the neurodegenerative process.

Experimental evidence suggests that ASIC1a could represent a new therapeutic target for neurodegenerative diseases. Below, we present the main ligands targeting ASIC1a, and the binding sites of ASIC1a are illustrated in Figure 1.

Neurodegenerative diseases are characterized by different and multifactorial processes sharing accumulation of misfolding proteins, damage of specific neuronal populations, and chronic inflammation state neuroinflammation. Another common feature is the shift to the acidic pH in the brain, which might contribute to apoptosis, protein misfolding, excitotoxicity, and neurodegeneration (Parton et al., 1991; Bender et al., 1997; Ding et al., 2000; Liu et al., 2012; Wang et al., 2012).

Emerging evidence supports the role of ASIC activation in several physiological processes such as synaptic plasticity and memory. On the other hand, ASICs are implicated in the pathophysiology of inflammatory and neurodegenerative diseases including PD, MS, AD, and HD.

The complex molecular pathways leading to neurodegeneration makes the search for novel effective agents difficult. In this frame, the development of potent and specific blockers for individual ASIC subunits, as well as the targeting of endogenous signaling molecules modulating the function of ASICs, might represent a new approach for the treatment of neurodegenerative conditions.

DM conceived the idea and prepared the manuscript. RN reviewed the drafts. Both authors contributed to the writing and approved final version of the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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