ASIC1, ASIC2, and ASIC3 have been detected in the astrocytes [77]. ASIC1 contributes to rapid depolarization of astrocytes, whereas ASIC2 and ASIC3 generate sustained currents and thus are slowly depolarizing [77]. Of these, ASIC1a is the most prevalent ASIC in human astrocytes [78]. ASIC1a colocalizes with other ion channel subunits, including α and γ ENaC, to form a channel on the plasma membrane of astrocytes and induce depolarization upon stimulation [79]. ASIC1a physiologically functions by allowing the influx of Na⁺ and Ca²⁺ ions when pH levels drop below 7.0 [78]. In astrocytes, such depolarization and signaling might be fundamental to the aforementioned functions of motor coordination [52,59,80], ROS mediation [60,81], and blood flow regulation [61,82]. However, the exact role of ASIC1a in astrocytes is not certain, and future studies would need to directly focus on this using astrocyte-specific genetic methods in order to determine its significance in physiology and pathology. Furthermore, the specific role of ASIC2 and ASIC3 in astrocytes is yet to be elucidated.

One feature that distinguishes functional ASIC1a from other ASIC components is its unique permeability to Ca²⁺, in addition to Na⁺ [12,13]. Calcium influx occurs during activation of astrocytic ASIC1a, as well as trafficking ASIC1a to the cell membrane under acidic extracellular conditions [78]. Intracellular Ca²⁺ plays an important role in long-term potentiation (LTP), which is critical for synaptic plasticity that contributes to learning and memory by activation of ASIC1a in neurons [83,84,85]. Astrocytic ASIC1a might contribute to synaptic plasticity such as LTP and long-term depression (LTD). This can definitively be confirmed in future studies since ASIC1a knockout (KO) mice are available [83].

ASICs are involved in neurodegenerative diseases [26,86,87]. The following experiments highlight the role of ASICs in exacerbating disease states. Using EAE as the experimental mouse model of multiple sclerosis (MS), the role of ASIC1 in this pathological state was examined [88]. It was found that ASIC1 KO mice had less axonal degeneration than their wild-type (WT) mice counterparts, indicating that ASIC1 progresses the degenerative process of MS [88]. This was very similar to findings in mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a chemical model of Parkinson’s disease (PD) [89]. PD is characterized by loss of dopaminergic neurons in the substantia nigra, where ASIC1a components are also located [89]. When ASIC1a was inhibited by its very effect inhibitor PcTx1, neurons were protected from degeneration [89]. In transgenic mice with the mutated ataxin-1 gene, a phenotype corresponding to spinocerebellar type 1 ataxia was observed, ASIC1 KO mice presented with improved motor function under this phenotype [90]. ASIC1 KO mice also upregulate the ubiquitin-proteasome system, which has been implicated in decreased huntingtin-polyglutamine accumulation [91]. The improved function of mice with deletion of ASIC1 or inhibition of ASICs support the idea of protective effects under ASIC1 inhibition or disruption. While there is more literature focusing on ASIC1 in neurons, it is important to note that ASIC1 has also been discovered in astrocytes. This puts forth the question of the exact role that astrocytic ASIC1 may play in conditions such as neurodegeneration. It is possible that ASIC1 in astrocytes is the primary channel disrupting homeostasis in these pathological conditions, but ASIC1 in neurons, oligodendrocytes, and microglia could also shape axonal structure and integrity. Therefore, astrocyte-specific deletion using conditional KO mice by crossing astrocyte-specific Cre driver mice such as GLAST-CreERT2, GFAP-CreERT2, and ALDH1L1-CreERT2 lines with floxed ASIC1 mice would be necessary in order to distinguish the specific function of ASIC1 in astrocytes.

In a mouse MCAO model, ASIC1a demonstrated a role in ischemic brain injury due to its calcium-dependent or calcium-independent mechanisms [13,92]. Activation of ASIC1a by acidosis, as a consequence of ischemic brain injury, leads to elevated intracellular calcium which contributes to pathological distress [13]. Additionally, the acidic environment created by strokes also causes ASIC1a to couple with an enzyme, receptor-interacting serine/threonine-protein kinase 1, triggering neuronal death through necroptosis [93,94]. Increased protease activity as a result of stroke has been implicated in increased ASIC1a activation which further contributes to ischemic brain injury [95]. Given these findings, it follows that when ASIC1a is inhibited under ischemic conditions, neuroprotection is observed [13,96]. Future studies can concentrate on ASIC1a in astrocytes to localize specific cellular changes contributing to brain ischemia.

Finally, a role for ASICs in brain tumors has been established. ASIC1a is highly expressed in malignant gliomas [97,98] and selective inhibition of ASIC1a by PcTx1 leads to a decrease in the rate of glioma cell growth [99] and significant inhibition of glioma cell migration [79,100]. Interestingly, ASIC2 in astrocytes inhibits the growth of gliomas [101]. When ASIC2 is not expressed, specific negative effectors requiring this channel are nonfunctional. This causes ASIC1 action to be unopposed, and leads to a basally-active cation current which characterizes glioma cells [101]. The results of these ASIC experiments demonstrate the integral role that ASIC1a has in accelerating glioma. In addition to neoplastic growth, ASIC1a activation is also a likely contributing factor to the high rates of epileptic seizures seen in glioma patients. This seizure-prone behavior is a consequence of extracellular acidosis which, in the absence of any neuronal signaling, induces ASIC1a depolarization in glioma cells and triggers electrical activity in brain circuits [102]. Furthermore, ASIC1a in gliomas induces electrical currents that promote cell proliferation, perpetuating the tumor prognosis [102]. This is confirmed by the fact that glioma proliferation and migration is inhibited by the ASIC1a inhibitor toxin, PcTx1 [79,97,98], as well as ASIC2 [101]. Therefore, ASIC1a in gliomas has widespread effects, through both malignancy of the cancer itself, as well as neurological side effects. Research focused on ASIC1a in astrocytes of gliomas may provide a direction in determining cellular targets to prevent cancer progression.

ASIC1a, 2a and 3 are expressed in microglial cells [103]. Another ion channel, voltage-gated proton channel (H_V) subtype 1, is prominently expressed in microglial cells and plays a role in free radical generation that contributes to ischemic brain injury [104]. Recent studies have confirmed that H_V1 is also involved in electrical signaling by activating ASIC1a in microglial cells, leading to further proton influx of Na⁺ and Ca²⁺ [105].

ASIC1a and ASIC2a contribute to the physiological function of microglial cells [87,103]. As was noted in the astrocyte section, ASIC1 is sensitive to small drops in pH; its threshold is around 7.0 [14,106]. ASIC2a, on the other hand, is not as sensitive to drops in pH and is only activated under much more acidic conditions, with a pH threshold of 5.5 for activation of ASIC2a homomers [14]. One of the physiological roles of ASIC2a is to increase ASIC1 co-localization to dendritic spines, facilitating normal neuronal function [107,108]. Without ASIC2a expression, there is less ASIC1 trafficking to cell membranes [107,108]. ASIC3 is primarily involved with pain modulation [15,21,109,110,111]. It has a pH threshold close to that of ASIC1 [4,112,113], and can be activated for experimental purposes by the non-proton ligand GMQ [23,24]. When ASIC3 is highly expressed in microglial cells due to low pH conditions, hyperalgesia to various insults is observed [114]. Furthermore, when ASIC3 is genetically deleted or inhibited by the peptide toxin, APETx2, fatigue-induced hyperalgesia is diminished [114].

The primary function of microglia is their role in environment surveillance and phagocytosis [63,115]. As microglia age, their execution in debris removal decreases; this dysfunction plays a major role in plaque formation. A_β plaque accumulation is characteristic of Alzheimer’s disease (AD) [116]. In addition to decreased efficacy in phagocytosis, aged microglia produce storms of inflammatory cytokines and ROS that create a positive feedback loop contributing to continued plaque formation and microglial dysfunction [116]. In particular, ASIC1 and ASIC2a are the most prevalent inflammatory respondents in microglia. This was demonstrated by the upregulation of ASIC1 and ASIC2a when stimulated by LPS, an inflammatory inducer [61,103]. Under LPS stimulation, when the nonspecific ASIC inhibitor, amiloride, or the selective ASIC1a inhibitor, PcTx1, were added, depolarization was prevented and there was reduced expression of inflammatory cytokines that activate enzymes such as nitric oxide (NO) synthase and cyclooxygenase 2 [103]. Such findings demonstrate how ASIC1 and ASIC2a in microglial cells contribute to cytokine storms. Consequently, when inflammation is overstimulated and causes overaccumulation of inflammatory cytokines and cellular debris, cellular senescence and neurodegeneration pursue [117].

Our recent study focusing on ASIC2 pathogenesis in ischemic brain injury found that in hippocampal, cortical, and striatal neurons, deletion of ASIC2 reduced surface ASIC1a levels, acid-activated current density, and acidosis/ischemia-induced neuronal injury [108]. We also found that, in cerebellar neurons with much less ASIC2 expression, ASIC2 deletion had no effect on surface ASIC1a level, acid-activated current density, or acidosis/ischemia-induced neuronal injury, suggesting that heteromeric ASIC1a/2 channels in certain brain regions are likely to contribute to ischemic brain injury [108]. With the established connection between ASIC1a and ischemic brain injury, these findings open the door for future research surrounding neuromodulation of ASIC2 to help mitigate neuronal injury after stroke. This could play an important role in targeted therapy due to the fact that there is a region-specific difference in the pathophysiology of ASIC2. Due to ASIC2 KO mice used in these studies, one possibility is that microglial ASIC2 is involved in this process. However, future studies need to explore whether microglial ASIC2 is directly involved in the ischemic brain injury.

Expression of ASIC3 in response to stimuli induces primary and secondary hyperalgesia [87]. Thus, pain associated with primary inflammation or inflammation induced by microglial dysfunction (as seen in AD) could potentially be attributed to ASIC3. Future research concentrated on the role of ASIC3 in microglial cells could provide evidence for therapeutic targeting against this cellular channel to diminish pain associated with certain neurological conditions.

Using imaging and immunofluorescence techniques, it has been determined that ASIC1a, ASIC2a, and ASIC4 mRNAs are expressed in oligodendrocyte lineage cells (OLC) [118]. When oligodendrocytes are treated with PcTx1, a selective inhibitor for ASIC1a, electrical currents are almost completely blocked as well, indicating a high expression of ASIC1a in OLC [118]. This proves that ASIC1a is found extensively in oligodendrocytes, and thus plays a substantial role in white matter function.

Oligodendrocytes serve primarily to form myelin sheaths which enhance electrical conduction of synaptic transmissions in the brain [57]. NG2-glia, also known as oligodendrocyte precursor cells (OPC), function to give rise to mature oligodendrocytes that then allow for myelin sheath formation [119]. OPC also forms tight homeostatic networks that maintain cell numbers. Thus, they are very effective for repopulation [52]. ASIC1a is the predominant ASIC component found in OPC and mature oligodendrocytes [119]. ASIC1a plays a significant role in the signaling pathways of OLC [118], which ultimately leads to myelin production and rapid saltatory conduction.

Oligodendrocyte dysfunction is implicated in several disease processes, most notably multiple sclerosis (MS) [120]. MS is characterized as an autoimmune disease resulting in progressive demyelination of CNS axons, ultimately leading to severe neurological pathology [121]. One proposed mechanism relates to the propensity for ASIC1 oligodendrocytes to be highly susceptible to calcium overload [122,123]. Recent studies show that ASIC2 also contributes to MS [124]. Using the EAE model in ASIC1 and ASIC2 KO mice, a significant reduction in clinical scoring was found not only in ASIC1 KO mice, but also in ASIC2 KO mice at days 20–23 after immunization [124]. The underlying mechanism of ASIC1a involved in MS might be due to activation of ASIC1a resulting in overload of intracellular Ca²⁺ in the EAE model [123]. Modulation of ASIC1a surface expression by deletion of ASIC2 might also contribute to MS [108], but this should be investigated in future studies.

OPC plays an important role in chronic conditions such as obesity and cancer [125,126]. OPC makes contact with leptin receptors on dendritic processes, which helps to regulate the electrical response of leptin in the body [125]. Since ASIC1a is prominently found in OPC [119], it can be postulated that ASIC1a holds a significant role in leptin signaling. When OPC is destroyed or ASIC1 in OPC are not functioning properly, obesity risk is hypothesized to increase [125]. Furthermore, OPC proteins are highly expressed in gliomas and are shown to promote tumor origination and progression [126]. Again, since ASIC1a is predominantly found in OPC, it can be predicted that this channel plays a specific role in OPC function. A direct focus on this in future studies would be necessary to confirm.