Purinergic receptors, particularly P2X receptors, have been a focus of extensive research originating from three distinct lines of investigation, each contributing to our understanding of their roles in physiological and pharmacological contexts (Young, 2010). These investigations include the study of junction potentials in smooth muscle cells, the role of ATP as a sympathetic transmitter in the bladder and vas deferens, and the action of exogenous ATP on cells such as mast cells, leading to the discovery of P2X and P2Z receptors (North, 2016). P2Z receptors were later identified as P2X7 receptors by IUPHAR (Di Virgilio et al., 2023; Abbracchio et al., 2023).

Purinergic signaling involves extracellular adenosine triphosphate (eATP) and its metabolites, adenosine diphosphate and adenosine, which activates Purinergic 1(P1R) and 2 (P2R) receptors. P2R comprises of P2Y, a G-protein-coupled receptor (GPCR) and intrinsic ion channels with ligand gates and P2X subtypes(Di Virgilio et al., 2018). Different types of purinergic receptors, including P2X4, P2X7, P2Y1, P2Y2, and P2Y4, are distributed across various ocular layers (Fig. 1), each playing distinct roles and targeting specific pathways, such as modulating inflammation, ATP release, and ocular surface damage, thereby influencing disease progression and therapeutic outcomes (Wang et al., 2023). P2X7R is crucial in inflammation by strongly stimulating the oligomerizing Nucleotide-binding Leucine-rich Pyrin containing Protein 3 (NLRP3) inflammasome, Interleukins production and release, and immune system activation. P2X7 receptor (P2X7R), a notable P2X receptor which functions as a non-selective ion channel that mediates cation influx and pore formation (Guerra Martinez, 2019).

Fig. 1 illustrates the distribution of purinergic receptors within the various structures of the eye. Specifically, it highlights the presence of P2Y1, P2Y2, P2Y4, and P2X7 receptors across the corneal epithelium/endothelium, iris, conjunctiva, ciliary body, and iridocorneal angle/trabecular meshwork. These receptors play critical roles in ocular physiology, including intraocular pressure regulation, aqueous humour dynamics, and inflammation, contributing to the overall maintenance of eye health and function. The distribution of P2X and P2Y receptor isoforms in Fig. 1 is derived from multiple sources, including immunohistochemical and in situ hybridization studies, transcriptomic datasets, and published receptor localization maps across ocular tissues. Receptor expression has been confirmed at both the RNA and protein levels in different studies, and the figure represents a compiled synthesis based on the most consistent findings across human and animal models (Suzuki-Kerr et al., 2008; Pintor et al., 2004).

P2X7R is a ligand-gated cation channel being trimeric having a chalice-like structure. It isabundantly dispersed in various tissues and cell types, including hematopoietic and mesenchymal stem cells, ocular, leukocytes, osseous, dental pulp, endothelial, muscular, renal, and integumentary cells and also in the Brain and Spinal nervous system. The P2X7 receptor gene (P2RX7) is located on chromosome 12q24 and encodes a protein of 595 amino acids with two transmembrane domains (TM1 and TM2), a large extracellular ligand-binding loop, and an extended intracellular C-terminal domain. The mRNA transcript size is approximately 2.6 kilobases (kb). Its unique structure enables pore dilation and downstream signaling upon ATP binding (Kawate et al., 2009; Gil-Redondo et al., 2022). Activation of P2X7R triggers a range of pathophysiological processes which are characteristically homeostatic and degenerative. These include the release of interleukins by activation of the inflammasome, cell surface molecular shedding by stimulation of metalloproteases, and mediation of fusion of phagosome and lysosome, autophagy, and generation of Oxygen free radicals such as Reactive Oxygen Species (ROS) to combat intracellular pathogens. Paradoxically, P2X7R activation promotes cell proliferation and cell death. Moreover, the expression of these receptors in microglia can promote excitotoxicity in neural cells by inducing glutamate release (Andrejew et al., 2020). Previous studies have highlighted the complex participation of P2RX7 in autoimmune arthritis and metabolic regulation, demonstrating both pro-inflammatory and negligible effects depending on the context (Felix et al., 2019; Tian et al., 2020).

The receptor can be pharmacologically modulated by various antagonists and positive modulators, offering potential therapeutic values for conditions ranging from inflammation to cancer. It is primarily activated by eATP, with concentrations up to 2.5 mM, based on the tissue specific species (He et al., 2013; Li et al., 2014). Additionally, synthetic ATP analogues such as 2-(3-)-O-(4-benzoylbenzoyl) adenosine triphosphate (BzATP) and adenosine 50-(γ-thio)-triphosphate can also activate the receptors, albeit with varying potency across species (Lopez-Castejon et al., 2007; Spildrejorde et al., 2014). LL-37, a cathelicidin-derived antimicrobial peptide, and other compounds such as tenidap, polymyxin B, clemastine, ivermectin, and ginsenosides, can modulate its activation (Elssner et al., 2004). Intracellular lipopolysaccharides (LPS) can facilitate P2X7R activation by stimulating caspase-11 and Pannexin-1 (PANX1), thereby increasing eATP levels (Elssner et al., 2004; Sanz et al., 1998; Ferrari et al., 2004; Norenberg et al., 2011; Helliwell et al., 2015; Yang et al., 2015). However, specific antagonists and blockers can inhibit P2X7R activity for which, various small molecules and biologics, including monoclonal antibodies and nanobodies, have been developed for this purpose (Reichenbach and Bringmann, 2016; O'Neal and Luther, 2024). Crystal structure analyses have provided insights into the binding pockets of P2X7R antagonists, aiding in the development of more specific drugs targeting this receptor. These analyses have identified an antagonist-binding pocket in P2X7R, offering insights into its mechanisms of antagonism and specificity. P2X7R is also implicated in glucose and lipid metabolism, modulation of gut microbiota, and functions as a surface receptor mediating phagocytosis independently of ATP activation. Overall, it plays pivotal roles in inflammation, immune response, cell proliferation, death, and metabolism, making it a crucial focus for understanding and treating various physiological and pathophysiological processes (Sluyter, 2017). PANX1 refers to pannexin-1 channel proteins that facilitate ATP release and are not themselves signaling pathways.

Fig. 2 shows the pathway of visual signals in the retina, highlighting the role of ATP and P2X7R in cell physiology and death. Extracellular ATP release activates P2X7R in RPE cells, leading to the formation of inflammasomes, ROS etc., causing apoptosis which results in rod cell death. Visual signals are transmitted from photoreceptors to bipolar cells and then to ganglion cells through P2X7R. The activation of P2X7 receptors in ganglion cells by ATP can induce cell death, impacting visual signal transmission. The inset shows the detailed structure of the retina. Not all cell types confirmed to express P2X7R are shown in Fig. 2 due to visual constraints; however, their expression is supported by immunohistochemical and transcriptomic data.

In the retina, P2X7R expression has been confirmed in several cellular groups (Fig. 2), including photoreceptor cells, retinal ganglion cells (RGC), amacrine cells, macrophages, microglia, Muller cells (MC), pericytes, astrocytes, and the retinal pigmented epithelium (RPE) (Reichenbach and Bringmann, 2016). P2X7R is involved in both photoreception and signal transmission processes in the retina, and it plays a multifaceted role in modulating visual output and the degeneration of RGCs (Sanderson et al., 2014). Specifically, purinergic signaling mediated by P2X7Rs in the plexiform layer influences photoreceptor function. Activation of P2X7Rs by the agonist BzATP amplifies a-wave, suggesting their part in modulating photoreceptor activity and emphasizing the importance of purinergic signaling in maintaining photoreceptor integrity (Chavda et al., 2016a). Regarding signal transmission, P2X7Rs are implicated in the visual signal modulation within the inner retina. They are expressed by amacrine cells, where they colocalize with neurotransmitters such as Gamma-Aminobutyric Acid (GABA). P2X7R activation can potentiate the A17 GABAergic amacrine cells and promote GABA release from them into rod bipolar cells, influencing complex pre-synaptic processing in the inner retina (Puthussery and Fletcher, 2004). Studies in human retinal explants confirm the involvement of P2X7R in RGC death. Interestingly, P2X7R antagonists can mitigate RGC loss triggered by ischemic conditions, suggesting a potential therapeutic avenue. The balance between ATP-induced excitotoxicity via P2X7Rs and the neuroprotective effects of adenosine, particularly through A1 and A3 receptors, further underscores the complex interplay of purinergic signaling in retinal function and pathology (Hartwick et al., 2004; Niyadurupola et al., 2013; Zhang et al., 2006). Additionally, P2X7R activation or blockade can modulate RGC responses to visual stimulation.

P2X7R is crucial in RGC degeneration, a central process in conditions such as glaucoma (Beckel et al., 2014). Stimulation of P2X7Rs by agonists such as BzATP induces RGC death through increased intracellular calcium (Ca2+) and caspase activation (Zhang et al., 2005). Intravitreal administration of BzATP results in RGC loss, which can be prevented by P2X7R antagonists (Hu et al., 2010). However, excessive ATP release, such as during photoreceptor cell death, can lead to rapid loss of photoreceptors. This degeneration can be attenuated by P2X7R antagonists, indicating a crucial involvement of the receptor in maintaining photoreceptor physiology (Puthussery and Fletcher, 2009).

The current review aims to identify the mechanism of P2X7 receptors (P2X7Rs) in the disease pathophysiology and progression on various retinal degenerative conditions, such as age-related macular degeneration (AMD), Behçet's disease (BD), Retinitis pigmentosa (RP), Diabetic Retinopathy (DR), Glaucoma, Uveitis, Stargardt's disease (STGD1), and Toxoplasmosis. Additionally, the article evaluates the therapeutic potential of targeting P2X7Rs by investigating the effects of P2X7R modulation on disease outcomes in both preclinical models and clinical studies, aiming to identify novel treatment strategies for the above-mentioned retinal conditions.