Purpose of Review

Considerable interest has been paid to purinergic receptors, a group of cell surface receptors that react to extracellular purines like adenosine and ATP, as possible biomarkers in a variety of physiological and pathological states. The P2X purinoreceptor 4 protein, which is encoded by the P2X4 gene, controls the microglial immune response and is linked to various aspects of brain illness. In the past ten years, P2X4 receptors have become known as possible therapeutic targets for CNS diseases.

Recent Findings

Purines can be synthesized with the salvage or de novo pathways and are crucial for cellular metabolism. For synaptic plasticity and signal transmission, the P2X4 receptor must be expressed at low levels in the central nervous system. Exocytosis, which secretes ATP-rich synaptic vesicles, causes an accumulation of ATP in the neuronal terminal, which activates P2X2 and P2X2/3 on the pre-synaptic side and P2X2, P2X4, and P2X6 on the post-synaptic side. When triggered with ATP, P2X4-mediated neuropathic pain is increased and produces brain-derived neurotrophic factor (BDNF). In vitro research on the P2X4 receptor is scant; however, it has been linked to neuropathic pain, inflammation, and alcohol use disease (AUD). Research from mouse models have suggested that an increase of P2X4 surface receptor in the hippocampus results in synaptic deficits and altered long-term potentiation (LTP) and long-term depression (LTD) recognized as a plasticity indicator. Interaction of both P2X4R and ATP also causes a massive release of brain-derived neurotrophic factor (BDNF), and in macrophages, it has a link with prostaglandin E2 (PGE2) release.

Summary

Ionotropic P2XR and metabotropic P2YR interact with each other to form complex signaling. In different cases of pathogenesis and in different tissues, ATP is found to be the key player, whose stimulation is found to activate the downstream signaling and transmission, and P2X4R is responsible for early inflammatory response. P2X receptors of different subunits are considered as promising targets for neuropathic pain because of their widespread availability/ expression in different tissues.