Ligand-Gated Ion Channels: Comparison
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Gliomas are common primary brain malignancies that remain difficult to treat due to their overall aggressiveness and heterogeneity. Although a variety of therapeutic strategies have been employed for the treatment of gliomas, there is increasing evidence that suggests ligand-gated ion channels (LGICs) can serve as a valuable biomarker and diagnostic tool in the pathogenesis of gliomas. Various LGICs, including P2X, SYT16, and PANX2, have the potential to become altered in the pathogenesis of glioma, which can disrupt the homeostatic activity of neurons, microglia, and astrocytes, further exacerbating the symptoms and progression of glioma. Consequently, LGICs, including purinoceptors, glutamate-gated receptors, and Cys-loop receptors, have been targeted in clinical trials for their potential therapeutic benefit in the diagnosis and treatment of gliomas.

  • glioma
  • ligand-gated ion channels

1. Cells Involved in Glioma Pathogenesis

Ligand channels play a role in the pathogenesis of various gliomas and serve as biomarkers in prognosis [21,22][1][2]. These channels, including P2X, SYT16, and PANX2, have a unique impact on cell types involved in gliomas, including neurons, microglia, and astrocytes. Throughout glioma formation, pathogenesis tends to alter these LGICs, inducing specific effects within each cell type that often promote tumorigenesis.

1.1. Neurons

Recently, neurons have become important contributors to glioma progression. Neuronal LGICs such as AMPAR, NMDAR, and GABAA have been implicated in tumorigenesis [23,24][3][4]. AMPARs are calcium ligand-gated channels that are overexpressed in gliomas, particularly the GluR1 and GluR4 subunits, and play a role in malignancy [23,25][3][5]. Studies have shown the pro-tumorigenic effect of AMPARs is potentially caused by their regulation of glutamate-induced calcium oscillations, leading to an overload of extracellular glutamate [23,26][3][6]. Glutamate is known to further promote neuronal and oligodendrocyte migration during development, displaying the potential for upregulated AMPAR to indirectly promote glioma migration [27][7]. Regarding the impact of AMPARs on gliomas, GluR1 expression has been shown to be associated with changes in glioma cell shape [23][3]. In GluR1 overexpression, staining has shown increased actin polymerization and focal adhesion to type 1 collagen, potentially proving attenuated extracellular matrix (ECM) binding and tumor migration [23][3].
Interestingly, AMPAR/NMDAR activation typically induces cell death in neurons, but paradoxically in glioma cells, glutamate-receptor activation promotes proliferation and invasion. Recent research has considered that glioma cells downregulate these ligand channels to optimize survival in a glutamate-abundant environment [28][8]. Uniquely, the majority of AMPARs and NMDARs within gliomas are on cells at the invasive front of the tumor [29][9].
Like AMPARs, NMDAR ligand channels play a pivotal role in neuronal survival but have also been seen to enhance the growth of gliomas [30][10]. NMDARs are composed of two GluN1 subunits, two GluN2A-D subunits, and potential GluN3 subunits, which vary depending on the localization within the brain [31][11]. These channels work via activation of the calcium/calmodulin kinase (CaMK-II/IV) and the mitogen-activated protein (MAPK) pathways leading to the eventual expression of early response genes (ERGs) [32,33][12][13]. Studies have shown that NMDAR activation leads to topoisomerase-2-beta (T2B) induced double-stranded breaks in ERGs and that improper repair of these DSBs can induce carcinogenesis and disease [34][14]. Regarding their implication in gliomas, overexpression of NMDARs is associated with worse prognosis in tumor patients [30,35][10][15]. Specifically, the T2B mediated DSBs eventually lead to the expression of proto-oncogenes cFOS and ERG1, which are associated with radioresistance and worse prognosis in gliomas [30][10]. T2B has also been seen to be overexpressed in glioma-initiating cells, suggesting an alteration of NMDAR activity by gliomas [36,37][16][17]. Further, subunit GluN2B has also shown relevance in tumor initiation showing the potential for therapeutic targeting of NMDAR function in the future [35][15].

1.2. Microglia

Microglia are the cells responsible for the CNS immune response. Like neurons, microglia express a variety of LGICs to help communicate with their environment. Particularly, the P2X purinergic receptor and several glutamate receptors play a prominent role in microglial-neuronal crosstalk [38][18]. It has been shown that GBMs and gliomas show strong upregulation of P2RX7 [39][19]. Subsequent studies have shown the association between P2RX7 inhibition and the reduction of tumor enlargement within gliomas [40][20]. P2RX7 confers a unique cell growth advantage via pumping up energy stores due to its ability to activate cation channels at low ATP concentrations [41][21]. Studies have shown the ability for transfection of P2RX7 to promote growth, potentially by the expression of factors involved in tumor progression and metastasis [40,41,42][20][21][22]. Currently, it is known that P2RX7 has a unique impact on the mitochondrial promotion of growth during tumor progression [42][22]. However, P2RX7s have been shown to promote the release of pro-inflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, which would limit tumor growth [43][23]. It is not well known the impact that gliomas have on these ligand-gated channels, but they could potentially include a role in triggering matrix metalloproteinase 2 (MMP-2). Through this mechanism, tumors could evade ATP-induced cytotoxicity and P2RX7 at high concentrations [39][19]. However, further research is needed on the impact that gliomas have on the P2X ligand channel, as the unique changes that GBMs and other gliomas induce on P2RX7 are a potential therapeutic target for tumor progression.

1.3. Astrocytes

Astrocytes, a subset of glial cells, are the most abundant cells in the CNS and are vital in the function of the blood–brain barrier (BBB) [44,45][24][25]. Furthermore, astrocytes have been shown to mediate the recycling of neurotransmitters. Historically, astrocytes have been marked as non-excitable but recent research has unveiled their role in cell signaling through response to glutamate [45][25]. The use of ligand-gated channels such as ionotropic glutamate receptors allows astrocytes to respond to intracellular fluctuations in calcium [46,47][26][27]. They also have various ligand-gated calcium channels, which are known to be fundamental to CNS function. Astrocytes’ ability to induce gliosis, the process in which astrocytes repair tissue in response to CNS damage, is also used in response to GBM progression [48,49][28][29]. Interestingly, gliosis may contribute to tumor growth. Factors such as nuclear factor kappa-B (Nf-kB) potentially lead to the activation of tumor-associated astrocytes (TAAs) [50][30]. Further, ligands such as receptor activators of Nf-kB are seen to be produced by GBM cells leading to an eventual increase in TAAs [50][30]. Further ligands such as TGF-Beta also can promote glioma cell invasion [50][30]. Similarly, the sonic hedgehog (SHH) pathway portions are seen to be upregulated in gliomas [51][31]. Issues with signaling regulation of this pathway are associated with the initiation of brain tumors.
Regarding the role of astrocyte ligand channels in gliomas, the expression at the membrane of both tumor cells and astrocytes provides a potential cross-link and further promotes tumor progression [52][32]. This communication confers the ability of glioma cells to regulate both H+ and calcium concentrations, contributing to the epithelial–mesenchymal transition common in gliomas and leading to further survival of the glioma [52][32]. Recently, the calcium-regulated release of vesicles has been considered for gliotrasmission [53,54][33][34]. This crosstalk between gliomas and astrocytes via released vesicles is seen to be more common, and their ability to transport specific proteins promotes GBM progression. Specifically, chloride intracellular channel proteins (CLICs) are involved in glioma progression [55][35]. CLIC-1 medicated glioma expansion via secreted extracellular vesicle communication has been recently considered a therapeutic target due to CLIC-1′s upregulation correlating with worse prognosis in GBM patients [56][36].

2. Role of Chemotaxis in the Spread of Gliotic Changes

Chemotaxis, characterized by the migration of cells or organisms in response to an extracellular chemical gradient, plays a crucial role in the progression of gliomas [57][37]. In the presence of tumors from the brain and spinal cord, chemokine receptors constitute the vast majority of ligand channels frequently engaged in chemotactic events [58][38]. Chemokine receptors enable the binding of chemokines as a ligand, ultimately serving as a chemoattractant for neighboring glioma cells [59][39]. Simply put, in response to the chemical messages emitted by damaged cells, glial cells—such as astrocytes and microglia—relocate toward an afflicted injury site [60][40]. At the location of interest, glial cells emit additional chemical signals that attract supplemental cells, resulting in an overall increased inflammatory cascade [61][41]. This mechanism is of utmost interest to neurosurgeons, as the use of chemotaxis by tumor cells can result in secondary brain injuries in cases where the inflammatory response overwhelms surrounding healthy tissue [61][41]. As such, chemotactic pathways are thought to serve a crucial part in the rapid spread of gliotic changes, attesting to glioma’s invasive nature [57][37]. With this in mind, the aggressiveness of gliomas abetted by chemotaxis must be further scrutinized to comprehensively understand their prognosis and improve mortality rates amongst affected patients.

Role of Proteases

To physically infiltrate the blood vasculature, the induction of proteolytic degeneration via proteases is essential [62][42]. In particular, matrix metalloproteinases, cysteine cathepsins, and serine proteases are a series of proteases that aid in the cleaving of cell-adhesion components, such as epithelial (E)-cadherin, which results in the interference of cell-to-cell junctions [63,64][43][44]. Individual or group-mediated tumor cell migration is facilitated by the loosening of these cell connections, where the turnover of proteins in the ECM and basement membrane permits invasive cells to move into the surrounding tissue and vasculature [65][45]. Proteases are not only essential for the degradation of extracellular proteins, but they also have specialized processing roles that are important for cell signaling. For instance, proteases can activate growth factors and cytokines, which significantly increase chemoattraction, cell migration, and metastasis [66][46]. These distinct ways of protease-enhanced invasion are not mutually exclusive; rather, they likely work in tandem to increase the spread of cancer cells. All of these activities are closely controlled by a cascade of protease interactions, which allows for the regulation and amplification of proteolysis during the invasion [67][47]. Therefore, when certain of these protease families are pharmacologically inhibited or genetically abrogated, a significant decrease in cancer cell invasion has been reported [68,69][48][49]. Evidently, understanding the processes of chemotaxis in aggressive gliomas might lead to the development of novel therapeutic techniques for treating these tumors.

3. Role of Ion Channels in Glioma Cell Signaling

Glioma pathogenesis is influenced by the formation of tumor microtubules which enables direct communication between glioma cells [70][50]. In addition, various autocrine and paracrine mechanisms have the potential to encourage glioma development and progression. As such, faulty LCIG activity has the ability to significantly impact and alter intracellular signaling pathways implicated in glioma pathogenesis. For example, direct communication between glioma cells and neurons is mediated by functional bona fide chemical synapses [70][50]. These synapses are located on tumor microtubules and produce signals mediated by AMPA receptors, allowing for calcium-mediated glioma cell invasion and growth [70][50]. GBM tumors additionally have the ability to form networks mediated by tumor microtubules that allow for significant intratumoral communication [71][51]. As with low-grade gliomas, glutamatergic signaling mediated by AMPA receptors is associated with increased GBM invasion and proliferation [71][51]. Specifically, longitudinal time-lapse imaging in vivo revealed GBM transition over time to form interconnected networks that allow for tumor growth and invasion, a process mediated by glutamatergic activation of tumor microtubules [71][51]. Furthermore, EGFR signaling has the ability to enhance glutamate release from glioma cells [72][52]. Once activated, EGFR has the potential to phosphorylate GluN2B, a subunit of the NMDA receptor [73][53]. This results in enhanced NMDA signaling and glioma cell migration [73][53]. Thus, EGFR signaling plays a crucial role in intracellular communication between glioma cells.

4. Overview of PANX2 Channels

Examining biomolecular changes in glioma patients has led many scientists to investigate the role of PANX2 channels in gliomas [83,84][54][55]. PANX2 channels contain glycoproteins and form single membrane channels between cells in the central nervous system, particularly in astrocytes and microglia [85][56]. Their membrane topology is similar to connexin hemichannels, but PANX2 is often shown to be in heptamers and octomers [86][57]. They are unable to form proper gap junctions between cells when compared to connexins despite sharing similar sequence homologies. Due to PANX2 missing two cysteine residues [85[56][58],87], its channel is unable to adhere properly to other cells and transfer large molecules between neuronal cells [88][59]. However, more recent studies using expansive technology have shown tiny vesicles branching from PANX2 in proximity to actin filaments, leading to the idea of the transfer of much smaller molecules [89][60]. PANX2 also has functions in cell differentiation, inflammation, tissue remodeling, and wound healing [90,91][61][62]. PANX2 mRNA is restricted primarily to the cerebral cortex, cerebellum, temporal lobe, and medulla, suggesting PANX2 plays an important role in neuronal cell differentiation and communication [86,92][57][63]. PANX2 are more commonly found within the neuronal cells in their cytoplasm or within membrane-bound organelles, such as the mitochondria [93][64]. Although not highly researched, studies have shown that the role of PANX2 in ATP regulation during cancers might connect with the purinergic role of ATP in various neurological disorders [94][65]. Purinergic receptors have often functioned in neuroinflammatory responses. Rapid excretion of ATP from cancerous cells has been seen to further activate nearby microglial cells. Lohman et al. [88][59] used various clinical studies to examine the role of PANX2′s cellular release of ATP in regulating inflammation within the brain. Inflammatory responses and unregulated inflammation have been shown to promote glioma growth [88,95][59][66]. One experimental study analyzed the connection between PANX2 and cancer immune infiltrates using a technique called Tumor Immune Estimate Resource using NIH’s data portal [22][2]. Their research database showcased an increase in levels of PANX2 and correlated it with increased survival and better outcomes for glioma patients. After analyzing numerous clinical variables such as tumor type and radiation treatment, a model that predicted the possible outcome of a patient was created based on the varying levels of PANX2 in patients [22][2]. Significant reductions in PANX2 levels were reported, but subsequent analysis is still being conducted on this model [22][2]. Another team of researchers reported decreased or absent levels of PANX2 mRNA in cultured human glioma cells [93][64]. When compared to PANX2′s involvement in oncogenicity, High Throughput cDNA microanalysis showed that PANX2 acted similarly to tumor suppressor genes due to the reduction of tumor cells when PANX2 was restored to normal levels [93][64]. The use of anti-PANX2 antibodies showed negligible or limited PANX2 expression in human glioma cells [93][64]. The search for targeted therapeutic strategies or genetic therapeutic approaches to battling high-grade gliomas is vastly important. Despite this extensive research and clinical analysis, PANX2 has a void of uncertainty. New studies need to be implemented to examine its potential to provide care and treatments for patients battling life-threatening gliomas [96][67].

5. LGICs as a Clinical Target

5.1. Purinoreceptors

The P2RX7 has been the most studied of the purinoreceptors in regard to cancer proliferation and thus appears to be the most promising avenue for therapeutics [43][23]. Interestingly, activation of P2RX7s can both inhibit and promote tumor growth depending on the level of receptor activation. At median levels of activation, the P2RX7 induces cell proliferation. At high levels of extracellular ATP, P2RX7 mediates caspase-3 cleavage with subsequent membrane degradation and cell death [43,97][23][68]. As mentioned previously, P2RX7 activation is thought to promote immune response through the release of pro-inflammatory cytokines. This spectrum of activation has been therapeutically leveraged to treat glioma. For example, Douguet et al. [98][69] developed a P2RX7 agonist, HEI3090, which sensitized non-small cell lung cancer to immunotherapy, inducing tumor regression in 80% of cancer-bearing mice. Aside from reducing tumor burden, targeting purinoreceptors is a new avenue for mitigating cancer comorbidities. Other P2XR subtypes have been associated with cancer-related symptoms. One salient example is neuropathic and inflammatory pain secondary to cancer growth and inflammatory state, respectively. Specifically, the P2RX2 and P2RX3 receptor subtypes expressed on afferent neurons have been shown to mediate cancer-associated pain [94,99][65][70]. Using a P2RX3 and P2RX2/3 receptor antagonist, AF-353, Kaan et al. [100][71] were able to decrease bone cancer pain in a rat model.

5.2. Glutamate-Gated Receptors

The NMDA and AMPA glutamate receptors are amongst the most studied glutamate-gated receptors for their role in tumorigenesis [101,102][72][73]. There are anti-epileptic medications that have mechanisms of action at the site of the glutamate receptor that, in recent years, have been studied for their potential role in glioma treatment [103][74]. For example, Perampanel is a non-competitive AMPA glutamate receptor antagonist that is FDA-approved to treat partial onset seizures. In GBM cell lines, Perampanel has been shown to have antiproliferative effects via a decrease in glucose uptake, slowing cell metabolism [104][75]. Talampanel is an allosteric inhibitor of the AMPA receptor that is currently being studied for its role in treating seizures, ALS, Parkinson’s disease, and GBM. Vigabatrin is an irreversible GABA transaminase inhibitor used to treat refractory seizures and infantile spasms that are being studied for treating brain tumors and, more specifically, gliomas [105][76]. Beyond the treatment of gliomas, glutamate-gated receptors have been implicated in other disease processes and have varying clinical trials. Riluzole is a medication FDA-approved for the treatment of amyotrophic lateral sclerosis (ALS). Its mechanism of action is not well-established but is thought to involve the inhibition of voltage-gated ion channel release of glutamate [106][77]. AMPA receptor activation has been shown to increase pancreatic cancer cell invasion [107][78]. North et al. showed that human ovarian and small-cell lung cancer lines express NMDA receptors and are potential targets for treatment [108,109][79][80].

5.3. Cys-Loop Receptors

Like the glutamate-gated receptor superfamily, Cys-loop receptor agonists/antagonists are widely FDA-approved for other neurological diseases. One historical link is between benzodiazepines, which are GABAA agonists, and the proliferation of breast cancer. Valproic acid (VPA) is a commonly used anti-epileptic that has been repositioned in recent years to treat both adult and pediatric glioma (NCT00879437, NCT00302159). VPA’s mechanism of action is mainly through the increase of presynaptic GABA, but recent research has suggested that VPA is a histone deacetylase inhibitor that alters the acetylation pathways in human gliomas [111,112,113][81][82][83]. This mechanism is similar to the already commonly used anti-brain tumor therapy, TMZ. VPA has been studied in animals and cell lines as a radiosensitizer for glioma. It has been shown that VPA-enhanced radiation-induced cell death in the C6 rat glioma cell line [114,115][84][85]. Su et al. found that VPA use as a radiosensitizer was well-tolerated in pediatric DIPG but ultimately did not result in an overall survival benefit [116][86]. As with discussion of purinoreceptors, Cys-loop receptors have been leveraged to alleviate cancer-associated symptoms. Therefore, this relationship could be therapeutically leveraged to improve the quality of life for patients with brain tumors. For example, LGICs have also been associated with the development of glioma-related epilepsy (GRE) in diffuse glioma patients [117][87]. As such, GABAA modulators have been commonly used in both general epilepsy and GRE. In addition to its potential use in decreasing glioma proliferation, VPA has also been studied in regard to GRE. NCT03048084 is currently recruiting patients to see which anti-epileptic is most efficacious in GRE (NCT03048084). The combinatorial benefit of seizure prophylaxis and tumor suppression would make VPA a very potent therapeutic for patients with brain tumors.

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