Table 1

Receptors P2X2 family and neurodegenerative diseases

Receptor	Disease/organism	Brief overview	Reference
P2X7 P2X4	Parkinson’s disease Alzheimer’s disease	P2X7R expression is increased on microglia, astrocytes, and oligodendrocytes in neuroinflammatory conditions in the CNS. Activation of P2X7R by increasing the concentration of extracellular ATP released from damaged brain cells, promotes microglia activation and proliferation, and directly promotes neurodegeneration by inducing microglia-mediated neuronal death, glutamate-mediated excitotoxicity, and NLRP3 inflammatory activation, leading to initiation, maturation, and release of proinflammatory cytokines and generation of reactive oxygen species and nitrogen forms.	Territo and Zarrinmayeh (2021)
P2X7 P2X4	Parkinson’s disease Alzheimer’s disease	Activation of microglia leads to increased expression of P2X4 and P2X7 and suppression of P2Y12 receptor expression.	Di Virgilio et al. (2017)
P2X7 P2X4	Parkinson’s disease Alzheimer’s disease	An indicator of microglia activation of the proinflammatory M1 phenotype is the high expression levels of P2X4 and P2X7 receptors.	Burnstock (2006)
P2X7 A2A	Parkinson’s disease Alzheimer’s disease	Adenosine and ATP are modulators of neuroinflammatory reactions, oxidative stress, and cell death through activation of A2A and P2X7 receptors, respectively. ATP-dependent activation of P2X7Rs induces necrosis by promoting the formation and opening of nonspecific membrane pores, leading to loss of intracellular content and activation of the caspase pathway, causing apoptosis in glial cells.	Illes et al. (2019)
А2А	Huntington’s disease	The adenosinergic pathway plays a significant role in the etiology and progression of BC especially through the A2A receptor, as observed in patients and animal models.	Ollà et al. (2020)
P2X7R	Amyotrophic lateral sclerosis	Inflammation and autophagy play a crucial role in the pathogenesis of ALS, while several studies have identified a role for P2X7R in the pathogenesis.	Volonté et al. (2016)
P2Y6	Alzheimer’s disease, multiple sclerosis, Parkinson’s disease, stroke, frontotemporal dementia, and CNS tumors	Microglia expresses purinergic P2Y6 receptors. P2Y6R acts as a regulator of inflammation and phagocytosis. Stimulation of this receptor by its endogenous ligand UDP can trigger the production and release of a large number of cytokines and chemokines.	Anwar et al. (2020)
P2YX7	Parkinson’s disease Huntington’s disease	Changes in the expression and activity of purinergic receptors such as P2YX7 have been noted, suggesting a potential role for this system in the etiology and progression of the disease.	Oliveira-Giacomelli et al. (2018)
P2X7R	Alzheimer’s disease	Activation of P2X7R leads to the opening of nonselective cation channels the constant activity of which causes depolarization of mitochondria and plasma membrane, plasma membrane pore formation, plasma membrane ballooning, and production of reactive oxygen species. Similarly, P2X7R activation increases the release of TNF-α, IL-18, and IL-6 and induces apoptotic cell death, making P2X7R an attractive therapeutic target to reduce inflammation and ATP-induced apoptosis via P2X7R antagonism.	Woods et al. (2016)
P2X4R	Parkinson’s disease	Current thinking suggests that activation of microglia and the subsequent release of inflammatory factors, including interleukin-6 (IL-6), are involved in the pathogenesis of PD. The P2X4 receptor (P2X4R) is a member of the P2X superfamily of ATP-activated ion channels. Following chronic constrictor injury (CCI), repeated administration of a P2X4R antagonist reduces IL-6 levels, implying that P2X4R can modulate neuroglial activation and IL-6 release. It has been suggested that P2X4R may play an important role in the pathogenesis of PD by damaging dopamine neurons through some specific mechanisms.	Jurga et al. (2017)
P2Y6	Parkinson’s disease	UDP binding by P2Y6R leads to the activation of various biochemical pathways depending on the disease context and pathologic environment. P2Y6R normally stimulates phagocytosis. P2Y6R can participate in LPS-induced neuroinflammation. Blocking P2Y6R is seen as a therapeutic target for the treatment of PD and AD patients by inhibiting microglia-induced neuroinflammation.	X. Yang et al. (2017)