The P2X7 Receptor: Central Hub of Brain Diseases

Abstract

The P2X7 receptor is a cation channel activated by high concentrations of adenosine triphosphate (ATP). Upon long-term activation, it complexes with membrane proteins forming a wide pore that leads to cell death and increased release of ATP into the extracellular milieu. The P2X7 receptor is widely expressed in the CNS, such as frontal cortex, hippocampus, amygdala and striatum, regions involved in neurodegenerative diseases and psychiatric disorders. Despite P2X7 receptor functions in glial cells have been extensively studied, the existence and roles of this receptor in neurons are still controversially discussed. Regardless, P2X7 receptors mediate several processes observed in neuropsychiatric disorders and brain tumors, such as activation of neuroinflammatory response, stimulation of glutamate release and neuroplasticity impairment. Moreover, P2X7 receptor gene polymorphisms have been associated to depression, and isoforms of P2X7 receptors are implicated in neuropsychiatric diseases. In view of that, the P2X7 receptor has been proposed to be a potential target for therapeutic intervention in brain diseases. This review discusses the molecular mechanisms underlying P2X7 receptor-mediated signaling in neurodegenerative diseases, psychiatric disorders, and brain tumors. In addition, it highlights the recent advances in the development of P2X7 receptor antagonists that are able of penetrating the central nervous system.

Keywords: P2X7 receptor; P2X7 receptor antagonists; brain diseases; brain tumor; neurodegenerative diseases; psychiatric disorders.

FIGURE 1

P2X7 receptor splicing variants. The P2X7 receptor has 10 different isoforms derived from alternative splicing and mutations of the 13 exons of the gene. The P2X7A isoform is the native form, expressed in every mammal species. The detected alterative isoforms in humans are P2X7B, H and J, while in rodents, these are P2X7B, C, D and K. The mutations that lead to a stop codon insertion, originate a shortened P2X7 receptor at the carboxy-terminal domain and cannot form pores that induce cell death. P2X7G and H present a copy of exon 3 (N3) near the amino-terminal. Known basic functions for each isoform are described at the right site of the panel. Aminoterminal (NH⁺), Carboxyterminal (COO^–), Transmembrane passage 1 (TM1), Transmembrane passage 2 (TM2).

FIGURE 2

P2X7 receptor single nucleotide polymorphisms (SNP) in brain diseases. Various P2X7 receptor SNPs have been detected and studied in humans. The gene that encodes the P2X7 receptor is located at chromosome 12, and at least seven of the SNPs are related to neurological disorders, such as Alzheimer’s disease (AD), bipolar disorder (BD), anxiety, multiple sclerosis (MS), major depressive disorder (MDD) and Parkinson’s disease (PD). The red letters represent SNPs that potentialize the response of the P2X7 receptor upon binding to its ligand and generate increased cell death and worsening of diseases. Further, green letters are in line with decreased Ca²⁺ inflow due to loss of function of the P2X7 receptor, and usually lead to neuroprotection. The SNPs are named rs208294, rs7958311, rs1718119, rs2230912, rs28360457, and rs3751143. Created with BioRender.com.

FIGURE 3

Intracellular signaling pathways triggered by P2X7 receptor activity. The P2X7 receptor is assembled as a homotrimeric protein, and upon ATP binding, receptor subunits change their conformational state and open a pore for the entrance of cations, mainly Ca²⁺. In physiological conditions (left panel), the increase of intracellular Ca²⁺ concentration levels ([Ca²⁺]_i) leads to the activation of some kinases, like protein kinase C (PKC) and calcium-calmodulin kinase II (CaMKII), which phosphorylates and activates phosphoinositide 3-kinase (PI3K), extracellular signal-regulated kinases 1/2 (ERK1/2), protein kinase B (AKT) and glycogen synthase kinase 3 (GSK3). This signal transduction results in inhibition of apoptosis or increase of the transcription of cell survival related genes. In pathological conditions (right panel), such as in Alzheimer’s disease (AD), multiple sclerosis (MS), major depressive disorder (MDD) and Parkinson’s disease (PD), P2X7 receptor expression rates are increased. Activation of the P2X7 receptor in AD animal model results in increased release of interleukin 1β (IL-1β) and reactive oxygen species (ROS), and augmented inhibition of GSK3. IL-1β release depends on the formation of the NLRP3 inflammasome together with the activation of the nuclear factor kappa-light-chain-enhancer activated B cells (NF-κB). In ALS, P2X7 receptor activation also induces overproduction of ROS and ERK1/2 signaling. Administration of P2X7 receptor antagonists has been suggested to benefit specific features of AD, PD, MS, MDD, and BD, like improvement of behavior and neuroinflammation. Nevertheless, high concentrations of P2X7 receptor agonists may also enhance in vitro cytotoxic effects of temozolomide, a drug of choice for glioblastoma treatment. Created with BioRender.com.