P2x7

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Immune cells

Release of IL-10

Arthritis, irritable bowel syndrome

(or ionic current) fades away very rapidly (within a few hundred milliseconds) by a process termed desensitiza-tion. Desensitization does not occur, or is much slower at the other P2X receptors.

Activation of P2X7 Ion Channels

The P2X7 receptor is a most unusual ion channel in that it not only opens to allow bidirectional flux of cations in a manner similar to that described above for typical ionotropic receptors. However, it also dilates over several seconds to minutes to a size that allows the passage of molecules of either charge with size up to 900 Da. It is not known whether this is due to a true dilatation of the ion-passing pore region within the P2X7 receptor protein itself, or whether the P2X7 receptor couples to another protein which then transports the larger molecules. A further signaling event that is uniquely associated with P2X7 receptor activation includes dramatic, rapid alterations in the cell cytoske-leton due to re-arrangement of the actin filaments within the cell. This causes dynamic membrane blebbing of the cell, visually appearing as though bubbles are continuously forming and retracting. The physiological significance of these membrane blebs are unknown but they have been associated with "programmed" cell death, or apoptosis. The intracellular carboxy-terminal amino acids of the P2X7 receptor are required for the large pore formation and the membrane blebbing but not for its cation-selective ion channel function.

P2X Receptors and Sympathetic Neurotransmission (P2Xi and P2X2 Receptors)

P2Xj receptors are highly expressed on vascular smooth muscle in the gastrointestinal (GI) tract and on visceral smooth muscle of the urogenital system, particularly the bladder, vas deferens, and ureter (Table I). P2X2 receptors are equally highly expressed in the neurons that innervate these tissues, the sympathetic autonomic nerves. The functional role for P2X2 receptors in autonomic neurotransmission is not understood, but P2Xj receptors are now known to be

Vasoconstriction Diagram

FIGURE 2 Sympathetic innervation to GI blood supply requires P2X receptors. Diagram illustrates the sympathetic nerves supplying the GI vasculature; the sympathetic nerves corelease noradrenaline and ATP. ATP activates postsynaptic P2Xi receptors on the arteriolar smooth muscle to cause vasoconstriction. Noradrenaline released from these nerves acts only on presynaptic noradrenaline receptors which are present on the sympathetic nerve endings; the presynaptic action of noradrenaline alters the subsequent release of ATP.

FIGURE 2 Sympathetic innervation to GI blood supply requires P2X receptors. Diagram illustrates the sympathetic nerves supplying the GI vasculature; the sympathetic nerves corelease noradrenaline and ATP. ATP activates postsynaptic P2Xi receptors on the arteriolar smooth muscle to cause vasoconstriction. Noradrenaline released from these nerves acts only on presynaptic noradrenaline receptors which are present on the sympathetic nerve endings; the presynaptic action of noradrenaline alters the subsequent release of ATP.

the primarily, and in some cases, solely responsible for vasoconstriction or visceral smooth muscle contractions caused by sympathetic nerve activity. For example, male mice in which the P2Xj receptor gene has been deleted are infertile, because the sympathetic nerve activity no longer causes smooth muscle of the vas deferens to contract. Thus, no sperm is released from the vas although all other aspects of ejaculation are unaltered. Similarly, in the GI vasculature, the vasoconstriction produced by sympathetic nerve activity is due to the release of ATP onto P2Xj receptors on the vascular smooth muscle. In both of these cases, noradrenaline, which is the cotransmitter along with ATP, continues to be released and act effectively on its receptors. However, the noradrenaline released from these nerves acts on presynaptic nor-adrenaline receptors to alter the release of both noradrenaline and ATP, but it does not act on postsynaptic noradrenaline receptors present on the smooth muscle (Figure 2).

P2X Receptors and Sensory Pathways (P2X3 and P2X2/3)

Pain Pathways

ATP applied to sensory nerve terminals in the skin or tongue has long been known to elicit pain, specifically a tingling or burning sensation in humans. The molecular cloning and subsequent receptor localization studies revealed that the P2X3 receptor subunit is preferentially localized to a specific subset of sensory afferent fibers which innervate skin and viscera. Most of these sensory fibers are nociceptors, i.e., they are activated by noxious stimuli. Both homomeric P2X3 receptors and heteromeric P2X2/3 receptors are found at presynaptic and postsynaptic sites in this pathway (Figure 3). When ATP is released as a result of tissue injury, gross visceral distention, or even excess sympathetic activation, it activates the P2X3 and P2X2/3 receptors on the nociceptor terminals and initiates excitatory flow to the dorsal horn neurons in the spinal cord. Here, P2X receptors play modulatory roles in further processing of painful stimuli. Presynaptic P2X2 receptors are present on excitatory (glutamate) and inhibitory (glycine or y-aminobutyrate, GABA) interneurons and can be activated by ATP released from the incoming primary afferents and also when it is coreleased with GABA from GABA interneurons. Activation of these presyn-aptic P2X receptors increases the further release of transmitters onto the doral horn neurons. There are also postsynaptic P2X receptors on the dorsal horn neurons which can be activated by the release of ATP from the GABA interneurons. These inhibitory and excitatory effects contribute to the "spinal" processing of pain information prior to transmission to central perception areas of the brain (Figure 3).

Interneurons With Dendritic Spines

Glutamate excitatory interneuron

FIGURE 3 P2X receptors and pain pathways P2X2, P2X3, and P2X2/3 receptors play a role in pain perception. See text for further description.

Glutamate excitatory interneuron

FIGURE 3 P2X receptors and pain pathways P2X2, P2X3, and P2X2/3 receptors play a role in pain perception. See text for further description.

Afferent Reflex Pathways

P2X receptors are involved in the proper functioning of several visceral afferent reflexes; the micturation reflex is the best studied. The micturition reflex is initiated by bladder distention and subsequent contraction of the bladder and ureter smooth muscle. This distension releases ATP from the uroepithelium where it activates P2X3 and/or P2X2/3 receptors on the urothelial afferent nerve terminals to evoke neural discharge into spinal cord regions which, in turn, activate efferent parasym-pathetic nerves to bladder and ureter smooth muscle to complete the reflex loop.

P2X Receptors and Immune Cell Function (P2X7)

P2X7 receptors are most abundantly found on immune cells which become activated by tissue damage, inflammation, or infection, i.e., the so-called antigen-presenting cells of the immune system, primarily monocytes, and macrophage. Their synthesis and expression is increased in these cells when the immune response is triggered. Activation of P2X7 receptors by ATP released from damaged cells at sites of inflammation or infection leads to the release of pro-inflammatory mediators (cytokines); the most important of these pro-inflammatory cytokines is interleukin-1b (IL-1b). IL-1b can produce fever, further inflammation, cell, and tissue death. Agents that may block its release are highly sought after with regard to treatment or prevention of diseases such as rheumatoid arthritis and inflammatory bowel disease, and intensive research efforts are currently underway to identify antagonists which selectively target P2X7 receptors.

See Also the Following Articles

Cell Death by Apoptosis and Necrosis • Cytokines • Glutamate Receptors, Ionotropic • Glutamate Receptors, Metabotropic • Neurotransmitter Transporters •

Nicotinic Acetylcholine Receptors • P2Y Purinergic Receptors

Glossary cytokine A protein (usually interleukins or interferons) secreted by lymphoid cells that affects the activity of other cells and is important in controlling inflammatory responses.

dendrogram A diagram showing the relationships of items arranged like the branches of a tree.

exocytosis The release of a substance contained in a small sac (vesicle) within a cell by a process in which the membrane surrounding the vesicle fuses with the membrane forming the outer wall of the cell.

exon A discontinuous sequence of DNA that codes for protein synthesis and carries the genetic code for the final messenger RNA.

intron A length of DNA that is not expressed as an amino acid or messenger RNA.

ionotropic receptors Membrane receptors which are integral ion channels not requiring coupling via intracellular G proteins.

metabotropic receptors Membrane receptors which couple to hetero-trimeric G proteins in order to produce an effect.

nociceptor A sensory nerve which subserves the perception of pain.

Further Reading

Burnstock, G. (2000). P2X receptors in sensory neurones. British J. Anaesthesiol. 84, 476-488.

Le Novere, N., and Changeux, J. P. (2001). The ligand-gated ion channel database: An example of a sequence database in neuroscience. Phil. Trans. Roy. Soc. London, B. Biolog. Sci. 356, 1121-1130.

North, R. A. (2002). Molecular physiology of P2X receptors. Physiol. Rev. 82, 1013-1067.

Biography

Annmarie Surprenant is currently a Professor of Cellular Physiology at the University of Sheffield, United Kingdom. She has a long-standing history of research in the area of ion channel physiology. Her lab was the first to demonstrate that extracellular ATP is a synaptic transmitter in the nervous system and that ATP, not noradrenaline, was the neurotransmitter responsible for sympathetically mediated vasoconstriction in arterioles. These sets of findings led to her work over the past decade: the cloning and functional characterization of the ATP-gated P2X receptor-ion channels.

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Arthritis Joint Pain

Arthritis Joint Pain

Arthritis is a general term which is commonly associated with a number of painful conditions affecting the joints and bones. The term arthritis literally translates to joint inflammation.

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