P2rx3, encoding an ionotropic ATP receptor, is involved in various physiological and pathological processes. It is implicated in neural development, pain perception, and may be associated with the regulation of insulin secretion [2,3,7]. It participates in neuroactive ligand-receptor interaction pathways, which are crucial for neural communication [6]. Genetic models, such as knockout mice, are valuable for studying its functions.

In mice, P2rx3 is expressed by Type I spiral ganglion neurons (SGNs) and hair cells during SGN branch refinement. P2rx3 null mice show more complex SGN branching patterns around birth, though this mostly recovers by postnatal day 6. These mice also have an increased proportion of SGNs expressing Calb2, suggesting P2rx3 is necessary for normal Type I SGN differentiation and branch refinement [1]. In HT-22 cells, the regulatory function of Praja2, a RING E3 ubiquitin ligase, is mediated by the P2rx3/P2rx7 axis. Pja2 regulates cell development and Alzheimer's disease marker genes by inhibiting P2rx3 but promoting P2rx7 [4]. P2X3 receptors are a target in pain syndromes, and a P2X3 antagonist from spider venom shows antinociception in animal models without dysgeusia, highlighting the importance of P2rx3 in pain-related research [5]. In human embryonic stem cell-derived neural precursor cells, ethanol exposure significantly reduced P2rx3 levels in undifferentiated cells but induced its mRNA and protein levels in differentiated cells, potentially related to enhanced nociceptive response [6].

In summary, P2rx3 plays essential roles in neural development, especially in SGN branch refinement and differentiation. Its involvement in pain perception and response to ethanol-induced changes makes it a significant gene in the study of related pathologies. Mouse knockout models have been instrumental in uncovering these functions, providing insights into potential therapeutic targets for pain-related and neural-development-associated diseases.

References:

1. Wang, Zhirong, Jung, Johnny S, Inbar, Talya C, Faaborg-Andersen, Christian, Coate, Thomas M. 2020. The Purinergic Receptor P2rx3 is Required for Spiral Ganglion Neuron Branch Refinement during Development. In eNeuro, 7, . doi:10.1523/ENEURO.0179-20.2020. https://pubmed.ncbi.nlm.nih.gov/32675174/

2. Silva, Amélia M, Rodrigues, Ricardo J, Tomé, Angelo R, Rosário, Luís M, Santos, Rosa M. . Electrophysiological and immunocytochemical evidence for P2X purinergic receptors in pancreatic beta cells. In Pancreas, 36, 279-83. doi:10.1097/MPA.0b013e31815a8473. https://pubmed.ncbi.nlm.nih.gov/18362842/

3. Lin, Yi-Yu, Lu, Yan, Li, Chun-Yun, Wang, Jin, Yu, Ye. 2024. Finely ordered intracellular domain harbors an allosteric site to modulate physiopathological function of P2X3 receptors. In Nature communications, 15, 7652. doi:10.1038/s41467-024-51815-7. https://pubmed.ncbi.nlm.nih.gov/39227563/

4. Gong, Mengting, Ye, Shoudong, Li, Wen-Xing, Lu, Aiping, He, Kan. 2020. Regulatory function of praja ring finger ubiquitin ligase 2 mediated by the P2rx3/P2rx7 axis in mouse hippocampal neuronal cells. In American journal of physiology. Cell physiology, 318, C1123-C1135. doi:10.1152/ajpcell.00070.2019. https://pubmed.ncbi.nlm.nih.gov/32267716/

5. Oparin, Peter, Khokhlova, Oksana, Cherkashin, Aleksandr, Grishin, Eugene, Vassilevski, Alexander. 2024. Potent painkiller from spider venom antagonizes P2X3 receptors without dysgeusia. In Molecular therapy : the journal of the American Society of Gene Therapy, 33, 771-785. doi:10.1016/j.ymthe.2024.12.036. https://pubmed.ncbi.nlm.nih.gov/39960544/

6. Kim, Yi Young, Roubal, Ivan, Lee, Youn Soo, Mathiyakom, Nathan, Kim, Yong. 2016. Alcohol-Induced Molecular Dysregulation in Human Embryonic Stem Cell-Derived Neural Precursor Cells. In PloS one, 11, e0163812. doi:10.1371/journal.pone.0163812. https://pubmed.ncbi.nlm.nih.gov/27682028/

7. North, R Alan. 2003. P2X3 receptors and peripheral pain mechanisms. In The Journal of physiology, 554, 301-8. doi:. https://pubmed.ncbi.nlm.nih.gov/12832496/