P2RX4

P2X purinoceptor 4 is a is_associated_with::protein that in humans is encoded by the P2RX4 is_associated_with::gene.

The product of this gene belongs to the family of purinoceptors for ATP. Multiple alternatively spliced transcript variants have been identified for this gene although their full-length natures have not been determined.

The receptor is found in the central and peripheral nervous systems, in the epithelia of ducted glands and airways, in the smooth muscle of the is_associated_with::bladder, is_associated_with::gastrointestinal tract, is_associated_with::uterus, and arteries, in uterine is_associated_with::endometrium, and in fat cells. P2X4 receptors have been implicated in the regulation of cardiac function, ATP-mediated cell death, synaptic strengthening, and activating of the is_associated_with::inflammasome in response to injury.

Receptor Structure and Kinetics
The P2X4 subunits can form is_associated_with::homomeric or is_associated_with::heteromeric receptors. The P2X4 receptor has a typical P2X receptor structure. The is_associated_with::zebrafish P2X4 receptor was the first purinergic receptor to be crystallized and have its three-dimensional structure solved, forming the model for the P2X receptor family. The P2X4 receptor is a ligand-gated cation channel that opens in response to ATP binding. The P2X4 receptor has high is_associated_with::calcium permeability, leading to the is_associated_with::depolarization of the cell membrane and the activation of various Ca2+-sensitive intracellular processes. Continued binding leads to increased permeability to N-methyl-D-glucamine (NMDG+) in about 50% of the cells expressing the P2X4 receptor. The desensitization of P2X4 receptors is intermediate when compared to P2X1 and P2X2 receptors.

Agonists
P2X4</SUB> receptors respond to ATP, but not αβmeATP. These receptors are also potentiated by is_associated_with::ivermectin, cibacron blue, and is_associated_with::zinc.

Antagonists
The main pharmacological distinction between the members of the purinoceptor family is the relative sensitivity to the antagonists is_associated_with::suramin and pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (is_associated_with::PPADS). The product of this gene has the lowest sensitivity for these antagonists

Receptor Trafficking
P2X4</SUB> receptors are stored in is_associated_with::lysosomes and brought to the cell surface in response to extracellular signals. These signals include IFN-γ, is_associated_with::CCL21, is_associated_with::CCL2. is_associated_with::Fibronectin is also involved in upregulation of P2X4</SUB> receptors through interactions with is_associated_with::integrins that lead to the activation of SRC-family kinase member, Lyn. Lyn then activates PI3K-AKT and MEK-ERK signaling pathways to stimulate receptor trafficking. Internalization of P2X4</SUB> receptors is is_associated_with::clathrin- and is_associated_with::dynamin-dependent is_associated_with::endocytosis.

Neuropathic Pain
The P2X4</SUB> receptor has been linked to is_associated_with::neuropathic pain mediated by is_associated_with::microglia is_associated_with::in vitro and is_associated_with::in vivo. P2X4</SUB> receptors are upregulated following injury. This upregulation allows for increased activation of is_associated_with::p38 mitogen-activated protein kinases, thereby increasing the release of brain-derived neurotrophic factor (BDNF) from microglia. BDNF released from microglia induces neuronal hyperexcitability through interaction with the is_associated_with::TrkB receptor. More importantly, recent work shows that P2X4</SUB> receptor activation is not only necessary for neuropathic pain, but it is also sufficient to cause neuropathic pain.