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.

Hyperactivation of P2X7 receptors as a culprit of COVID-19 neuropathology

“…In addition, P2X7 receptor expression deletion appears to be beneficial in case of acute lung injury, asthma, lung inflammation, and fibrosis [ 87 – 91 ]. Remarkably, P2X7 receptor activation increases neuroinflammatory responses, which have been associated with neurodegenerative diseases, psychiatric disorders and stroke [ 21 , 92 – 95 ], as further discussed.…”

“…Since the P2X7 receptor is also involved in lung damage [ 87 – 89 ], neurodegenerative and psychiatric disorders [ 92 , 95 , 118 ], the hypothesis is reasonable that inhibition of this receptor might decrease pathological traits mediated by the RAAS pressor axis and protect against brain and lung injury in COVID-19 patients. Indeed, evidence demonstrates that P2X7 receptor blockade prevents Ang II-triggered pro-inflammatory responses [ 119 ].…”

“…The role of the P2X7 receptor in neuroinflammatory processes in neuropsychiatric and neurodegenerative diseases is widely studied [ 95 , 118 ]. In neurodegenerative diseases, cell death is accompanied by neuroinflammatory processes and massive ATP release [ 138 ].…”

Antagonistic Roles of P2X7 and P2Y2 Receptors in Neurodegenerative Diseases

“…Several BBB-permeant small molecule P2X7R antagonists were developed (for a review, see Andrejew et al, 2020), and some of them are undergoing clinical trials for the treatment of neurodegeneration: CE22,535, already tested in phase 2 and 3 clinical trials; and JNJ541754467 tested in a phase 1 clinical trial (for a detailed review, see Calzaferri et al, 2020). Therapeutic P2Y2R agonists include diquafosol (Lau et al, 2014) and Denufosol tetrasodium (Deterding et al, 2007).…”

Structural basis for the functional properties of the P2X7 receptor for extracellular ATP

“…The P2X7 receptor plays a critical role in mediating immune responses, bone remodelling, neuronglia communication, and other physiological processes, and is also important in the pathogenesis of many conditions, including autoimmune diseases, neurodegenerative diseases, mood disorders, and cancers, making it an attractive therapeutic target (e.g. [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24]).…”