P2rx4, also known as purinergic receptor P2X, ligand-gated ion channel 4, is a key molecule in the purinergic receptor X family. It is an ATP-gated ion channel involved in multiple biological processes. P2rx4 is expressed in various cell types such as structural cells (like alveolar epithelial and smooth muscle cells) and inflammatory cells (including macrophages, dendritic cells, T cells, and dorsal root ganglion neurons). It is associated with pathways related to immune protection, autophagy, glucose homeostasis, and pain processing, thus playing an important role in maintaining normal physiological functions and in disease-related processes [1,2,3,4]. Genetic models, like gene knockout (KO) mouse models, are valuable for studying its functions.

In KO mouse models, mutation of P2rx4 led to decreased serum antibodies and selective loss of bone marrow plasma cells, indicating its crucial role in immune protection as bone marrow plasma cells rely on P2rx4 to sense extracellular ATP released by osteoblasts [1]. P2rx4-deficient mice also showed alleviated allergen-induced airway inflammation, with reduced eosinophilia, Th2 cytokine production, and bronchial hyperresponsiveness, suggesting its contribution to the pathogenesis of allergic asthma [3]. In addition, sensory neuronal P2rx4-deficient mice had impaired BDNF-dependent signaling pathways in the spinal cord dorsal horn during peripheral inflammation, highlighting its role in chronic inflammatory pain [4].

In conclusion, P2rx4 is essential for multiple biological functions. Through model-based research, especially KO mouse models, we have learned that it plays a significant role in immune-related diseases such as those affecting bone marrow plasma cells and allergic asthma, as well as in chronic inflammatory pain. These findings provide potential therapeutic targets for treating these disease conditions.

References:

1. Ishikawa, Masaki, Hasanali, Zainul S, Zhao, Yongge, Allman, David, Bhandoola, Avinash. 2024. Bone marrow plasma cells require P2RX4 to sense extracellular ATP. In Nature, 626, 1102-1107. doi:10.1038/s41586-024-07047-2. https://pubmed.ncbi.nlm.nih.gov/38355795/

2. Li, Ruolin, Lu, Yongquan, Zhang, Qidi, Gao, Ge, Yang, Hui. 2021. Piperine promotes autophagy flux by P2RX4 activation in SNCA/α-synuclein-induced Parkinson disease model. In Autophagy, 18, 559-575. doi:10.1080/15548627.2021.1937897. https://pubmed.ncbi.nlm.nih.gov/34092198/

3. Zech, Andreas, Wiesler, Benjamin, Ayata, Cemil Korcan, Cicko, Sanja, Idzko, Marco. . P2rx4 deficiency in mice alleviates allergen-induced airway inflammation. In Oncotarget, 7, 80288-80297. doi:10.18632/oncotarget.13375. https://pubmed.ncbi.nlm.nih.gov/27863396/

4. Lalisse, Sarah, Hua, Jennifer, Lenoir, Manon, Rassendren, François, Ulmann, Lauriane. 2018. Sensory neuronal P2RX4 receptors controls BDNF signaling in inflammatory pain. In Scientific reports, 8, 964. doi:10.1038/s41598-018-19301-5. https://pubmed.ncbi.nlm.nih.gov/29343707/