P2RX4 Membrane Protein Introduction

Introduction of P2RX4

P2X purinoceptor 4 (P2RX4) is a membrane protein encoded by human P2RX4 gene, which is mapped to chromosome 12q24.31. P2RX4 is a member of the family of purinoceptors for ATP, also known as ATP-gated P2X receptor cation channel family. All P2X-receptors (including P2RX4) can be exclusively activated by ATP, which induces Ca²⁺ influx, causing changes in cell homeostasis. P2RX2 is widely expressed in different tissues and cell types, including cells of the reproductive system, in the airways, on microglia and cardiac myocytes as well as neutrophils, eosinophils, mast cells, T- and B-lymphocytes. P2RX4 can form chalice-shaped, trimeric channel, which is knitted together by subunit-subunit contacts.

Function of P2RX4 Membrane Protein

As an ATP-guided ion channel expressed in both macrophages and neurons, P2RX4 is involved in many neural processes, such as membrane depolarization, pain transmission, microglial cell migration, cardiac muscle contraction, regulation of protein kinase B signaling, etc. Indeed, afferent nerve lesions induce activation of microglial P2RX4 in superficial layers of the spinal cord leading to the modification of dorsal horn neurons (DHNs) excitability, which may affect the induction of chronic pain. In vivo and in vitro studies also showed that P2RX4 is a key player in the pain transmission. Besides its role in the nervous system, P2RX4 signaling is also shown to exert immunomodulatory functions such as inducing inflammatory-mediated prostaglandin E2 (PGE2) release, endothelial cell chemotaxis, and facilitating T cell activation at the immune synapse. It is reported that P2RX4 can interact with P2RX7 to regulate P2RX7 dependent IL-1ß and IL-18 release and to promote NLRP3 inflammasome activation. So, P2RX4 is an effective therapeutic target to treat pathological pain. P2RX4 antagonist has recently developed in a model of herpetic pain.

Fig.1 Crystal structure of zebrafish P2RX4 in trimeric form (4DW1). (Hattori, 2012)

Application of P2RX4 Membrane Protein in Literature

1. Ledderose C., et al. Purinergic P2X4 receptors and mitochondrial ATP production regulate T cell migration. J Clin Invest. 2018, 128(8): 3583-3594. PubMed ID: 29894310
   
   

   This article finds that P2RX4 can regulate T cell migration, suggesting that P2RX4 may be a potential therapeutic target for immunomodulation in inflammatory diseases and transplantation.

2. Csóka B., et al. Macrophage P2X4 receptors augment bacterial killing and protect against sepsis. JCI Insight. 2018, 3(11). PubMed ID: 29875325
   
   

   This article proposes that P2X4Rs may be a potential therapeutic target for drug discovery to repress bacterial growth in sepsis and other infections.

3. Zhu G., et al. Chronic lead exposure enhances the sympathoexcitatory response associated with P2X4 receptor in rat stellate ganglia. Environ Toxicol. 2018, 33(6): 631-639. PubMed ID: 29457680
   
   

   This article confirms that the up-regulation of P2RX4 expression in satellite glial cells (SGCs) of the stellate ganglion (SG) perhaps amplifies the sympathoexcitatory response induced by chronic lead exposure.

4. Le Guilcher C., et al. The P2X4 purinergic receptor regulates hepatic myofibroblast activation during liver fibrogenesis. J Hepatol. 2018, 69(3): 644-653. PubMed ID: 29802948
   
   

   This article finds that the purinergic receptor P2RX4 is involved in a previously unexplored pathway, which can mediate fibrotic liver repair, suggesting that P2RX4 may be a potential target in the development of novel therapies for fibrotic liver diseases.

5. Aby F., et al. Inflammatory-induced spinal dorsal horn neurons hyperexcitability is mediated by P2X4 receptors. Pain Rep. 2018, 3(3): e660. PubMed ID: 29922748
   
   

   This article confirms that P2RX4 plays a prominent role in inflammatory pain context and demonstrates that P2RX4 also play a role in the hyperexcitability of DHNs.

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Reference

1. Hattori M and Gouaux E. (2012). Molecular mechanism of ATP binding and ion channel activation in P2X receptors. Nature. 485: 207-212.

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