Purinergic (P2X) Receptors

P2X Purinergic Receptor Subunits

Each functional P2X receptor is formed from either three identical subunits (homomeric) or a combination of two or three different subunits (heteromeric). Except for P2X₆, all subunits can form homomeric receptors, however, P2X₇ subunits only form homomeric receptors. Functional receptors are named for their constituent subunits, for example a homomeric receptor composed of P2X₇ subunits is called a P2X₇ receptor, while a heteromeric receptor composed of P2X₂ and P2X₃ subunits is called a P2X_2/3 receptor.

Figure 1: Structure of human homomeric P2X₃ receptor. Structure taken from PDB. PDBID: 5SVQ. Mansoor et al (2016) X-ray structures define human P2X₃ receptor gating cycle and antagonist action. Nature 538: 66-71

Three molecules of ATP are required for channel opening, with one binding to each subunit. P2X receptors are highly selective for ATP over other purines and pyrimidines such as ADP and UTP, which activate P2Y receptors. ATP binding causes a conformational change in the ion channel structure that opens the pore and allows cations to pass through the cell membrane. The specific subunit confirmation of a receptor determines channel opening time; for example P2X₁ and P2X₃ receptors desensitize within a few 100 ms but for P2X₇ receptors there is little decrease in ionic current flow even over several minutes.

The subunit conformation of a receptor also determines its pharmacology; different subunits have different sensitivities to P2X agonists, such as ATP (Cat. No. 3245) and α,β-meATP (Cat. No. 3209) and P2X antagonists, such as PPADS (Cat. No 0625) and TNP-ATP (Cat. No. 2464). The sensitivity of a P2X receptor to ATP is heavily affected by changes in extracellular pH and by heavy metals, due to the presence of histidine side chains in the receptor's extracellular domains. An extracellular pH <7 attenuates ATP sensitivity at P2X₁, P2X₃ and P2X₄ receptors but increases P2X₂ receptor ATP sensitivity. In contrast, zinc potentiates ATP-gated currents through P2X₂, P2X₃ and P2X₄, and inhibits currents through P2X₁ receptors.

P2X Purinergic Receptor Distribution

P2X receptors have a wide distribution throughout the body and are found at neuromuscular junctions in the central and peripheral nervous system including the spinal cord, in smooth muscle, in the heart, and on leukocytes. In the brain, P2X receptors are found at pre- and post-synaptic membranes where they modulate neurotransmitter release. In general, different P2X receptor subtypes don't display tissue specificity and there is a large overlap in subunit distribution, with most cells expressing more than one receptor subtype.

Their extensive distribution means P2X receptors are involved in a diverse range of physiological processes, including modulation of synaptic transmission, modulation of vascular tone, cardiac rhythm and contractility, nociception and chronic pain, contraction of the bladder, and immune response.

P2X₇ receptors are of interest in cancer immunology as they are overexpressed in tumors. Elevated intratumoral ATP levels acting via P2X₇ receptors on myeloid-derived suppressor cells (MDSCs), result in immunosuppression.

P2X Purinergic Receptors & Nociception

P2X₃ and P2X_2/3 receptors have been well studied for their role in nociception. They are highly expressed on sensory neurons in dorsal root ganglia in the spinal cord, and are also found at nociceptive nerve terminal in the periphery where they respond to increased extracellular ATP from various sources including tumors and the vascular endothelium. Similarly, activation of P2X and P2Y receptors on glial cells (astrocytes and microglial) are thought to indirectly modulate nociception. Research has suggested that the expression of these receptors on nociceptive nerve terminals and glial cells contributes to the development and maintenance of various forms of neuropathic and inflammatory pain. The selective P2X₂ and P2X_2/3 receptor antagonist A 317491 (Cat. No. 6493) displays antinociceptive activity in multiple different pain paradigms including neuropathic, inflammatory and chronic pain states, in animal models.

External sources of pharmacological information for Purinergic (P2X) Receptors :

• IUPHAR Receptor Code

• BJP Guide

Literature for Purinergic (P2X) Receptors

Tocris offers the following scientific literature for Purinergic (P2X) Receptors to showcase our products. We invite you to request* your copy today!

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P2X and P2Y Receptors Scientific Review

Written by Kenneth Jacobson, this review provides an overview of the different subtypes and structures of the P2 receptor families, as well as the pharmacological probes used to study them; compounds available from Tocris are listed.

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P2X Receptor Gene Data