Purinergic receptor

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Purinergic receptors, also known as purinoceptors, are a family of plasma membrane molecules that are found in almost all mammalian tissues. [1] Within the field of purinergic signalling, these receptors have been implicated in learning and memory, locomotor and feeding behavior, and sleep. [2] More specifically, they are involved in several cellular functions, including proliferation and migration of neural stem cells, vascular reactivity, apoptosis and cytokine secretion. [2] [3] These functions have not been well characterized and the effect of the extracellular microenvironment on their function is also poorly understood.

Contents

The term purinergic receptor was originally introduced to illustrate specific classes of membrane receptors that mediate relaxation of gut smooth muscle as a response to the release of ATP (P2 receptors) or adenosine (P1 receptors). P2 receptors have further been divided into five subclasses: P2X, P2Y, P2Z, P2U, and P2T. To distinguish P2 receptors further, the subclasses have been divided into families of metabotropic (P2Y, P2U, and P2T) and ionotropic receptors (P2X and P2Z). [4]

In 2014, the first purinergic receptor in plants, DORN1, was discovered. [5]

3 classes of purinergic receptors

NameActivationClass
P1 receptors adenosine G protein-coupled receptors
P2Y receptors nucleotides G protein-coupled receptors
P2X receptors ATP ligand-gated ion channel

There are three known distinct classes of purinergic receptors, known as P1, P2X, and P2Y receptors. [What about P2Z,U,T?]

P2X receptors

P2X receptors are ligand-gated ion channels, whereas the P1 and P2Y receptors are G protein-coupled receptors. These ligand-gated ion channels are nonselective cation channels responsible for mediating excitatory postsynaptic responses, similar to nicotinic and ionotropic glutamate receptors. [6] P2X receptors are distinct from the rest of the widely known ligand-gated ion channels, as the genetic encoding of these particular channels indicates the presence of only two transmembrane domains within the channels. [1] These receptors are greatly distributed in neurons and glial cells throughout the central and peripheral nervous systems. [1] P2X receptors mediate a large variety of responses including fast transmission at central synapses, contraction of smooth muscle cells, platelet aggregation, macrophage activation, and apoptosis. [2] [7] Moreover, these receptors have been implicated in integrating functional activity between neurons, glial, and vascular cells in the central nervous system, thereby mediating the effects of neural activity during development, neurodegeneration, inflammation, and cancer. [2] The physiological modulator Zn2+ allosterically enhances ATP-induced inward cation currents in the P2X4 receptor by binding to cysteine 132 and cystine 149 residues on the extracellular domain of the P2X4 protein. [8] [9]

P2Y and P1 receptors

Both of these metabotropic receptors are distinguished by their reactivity to specific activators. P1 receptors are preferentially activated by adenosine and P2Y receptors are preferentially more activated by ATP. P1 and P2Y receptors are known to be widely distributed in the brain, heart, kidneys, and adipose tissue. Xanthines (e.g. caffeine) specifically block adenosine receptors, and are known to induce a stimulating effect to one's behavior. [10]

Inhibitors

Inhibitors of purinergic receptors include clopidogrel, prasugrel and ticlopidine, as well as ticagrelor. All of these are antiplatelet agents that block P2Y12 receptors.

Effects on chronic pain

Data obtained from using P2 receptor-selective antagonists has produced evidence supporting ATP's ability to initiate and maintain chronic pain states after exposure to noxious stimuli. It is believed that ATP functions as a pronociceptive neurotransmitter, acting at specific P2X and P2Y receptors in a systemized manner, which ultimately (as a response to noxious stimuli) serve to initiate and sustain heightened states of neuronal excitability. This recent knowledge of purinergic receptors' effects on chronic pain provide promise in discovering a drug that specifically targets individual P2 receptor subtypes. While some P2 receptor-selective compounds have proven useful in preclinical trials, more research is required to understand the potential viability of P2 receptor antagonists for pain. [11]

Recent research has identified a role for microglial P2X receptors in neuropathic pain and inflammatory pain, especially the P2X4 and P2X7 receptors. [12] [13] [14] [15] [16]

Effects on cytotoxic edema

Purinergic receptors have been suggested to play a role in the treatment of cytotoxic edema and brain infarctions. It was found that with treatment of the purinergic ligand 2-methylthioladenosine 5' diphosphate (2-MeSADP), which is an agonist and has a high preference for the purinergic receptor type 1 isoform (P2Y1R), significantly contributes to the reduction of an ischemic lesions caused by cytotoxic edema. Further pharmacological evidence has suggested that 2MeSADP protection is controlled by enhanced astrocyte mitochondrial metabolism through increased inositol triphosphate-dependent calcium release. There is evidence suggesting a relationship between the levels of ATP and cytotoxic edema, where low ATP levels are associated with an increased prevalence of cytotoxic edema. It is believed that mitochondria play an essential role in the metabolism of astrocyte energy within the penumbra of ischemic lesions. By enhancing the source of ATP provided by mitochondria, there could be a similar 'protective' effect for brain injuries in general. [17]

Effects on diabetes

Purinergic receptors have been implicated in the vascular complications associated with diabetes due to the effect of high-glucose concentration on ATP-mediated responses in human fibroblasts. [18]

See also

Related Research Articles

<span class="mw-page-title-main">Astrocyte</span> Type of brain cell

Astrocytes, also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of endothelial cells that form the blood–brain barrier, provision of nutrients to the nervous tissue, maintenance of extracellular ion balance, regulation of cerebral blood flow, and a role in the repair and scarring process of the brain and spinal cord following infection and traumatic injuries. The proportion of astrocytes in the brain is not well defined; depending on the counting technique used, studies have found that the astrocyte proportion varies by region and ranges from 20% to around 40% of all glia. Another study reports that astrocytes are the most numerous cell type in the brain. Astrocytes are the major source of cholesterol in the central nervous system. Apolipoprotein E transports cholesterol from astrocytes to neurons and other glial cells, regulating cell signaling in the brain. Astrocytes in humans are more than twenty times larger than in rodent brains, and make contact with more than ten times the number of synapses.

<span class="mw-page-title-main">Astrogliosis</span> Increase in astrocytes in response to brain injury

Astrogliosis is an abnormal increase in the number of astrocytes due to the destruction of nearby neurons from central nervous system (CNS) trauma, infection, ischemia, stroke, autoimmune responses or neurodegenerative disease. In healthy neural tissue, astrocytes play critical roles in energy provision, regulation of blood flow, homeostasis of extracellular fluid, homeostasis of ions and transmitters, regulation of synapse function and synaptic remodeling. Astrogliosis changes the molecular expression and morphology of astrocytes, in response to infection for example, in severe cases causing glial scar formation that may inhibit axon regeneration.

<span class="mw-page-title-main">Neuroimmune system</span>

The neuroimmune system is a system of structures and processes involving the biochemical and electrophysiological interactions between the nervous system and immune system which protect neurons from pathogens. It serves to protect neurons against disease by maintaining selectively permeable barriers, mediating neuroinflammation and wound healing in damaged neurons, and mobilizing host defenses against pathogens.

In the physiology of the kidney, tubuloglomerular feedback (TGF) is a feedback system inside the kidneys. Within each nephron, information from the renal tubules is signaled to the glomerulus. Tubuloglomerular feedback is one of several mechanisms the kidney uses to regulate glomerular filtration rate (GFR). It involves the concept of purinergic signaling, in which an increased distal tubular sodium chloride concentration causes a basolateral release of adenosine from the macula densa cells. This initiates a cascade of events that ultimately brings GFR to an appropriate level.

<span class="mw-page-title-main">P2X purinoreceptor</span>

The ATP-gated P2X receptor cation channel family, or P2X receptor family, is a protein family that consists of cation-permeable ligand-gated ion channels that open in response to the binding of extracellular adenosine 5'-triphosphate (ATP). They belong to a larger family of receptors known as the ENaC/P2X superfamily. ENaC and P2X receptors have similar 3-D structures and are homologous. P2X receptors are present in a diverse array of organisms including humans, mouse, rat, rabbit, chicken, zebrafish, bullfrog, fluke, and amoeba.

<span class="mw-page-title-main">Satellite glial cell</span>

Satellite glial cells, formerly called amphicytes, are glial cells that cover the surface of neuron cell bodies in ganglia of the peripheral nervous system. Thus, they are found in sensory, sympathetic, and parasympathetic ganglia. Both satellite glial cells (SGCs) and Schwann cells are derived from the neural crest of the embryo during development. SGCs have been found to play a variety of roles, including control over the microenvironment of sympathetic ganglia. They are thought to have a similar role to astrocytes in the central nervous system (CNS). They supply nutrients to the surrounding neurons and also have some structural function. Satellite cells also act as protective, cushioning cells. Additionally, they express a variety of receptors that allow for a range of interactions with neuroactive chemicals. Many of these receptors and other ion channels have recently been implicated in health issues including chronic pain and herpes simplex. There is much more to be learned about these cells, and research surrounding additional properties and roles of the SGCs is ongoing.

<span class="mw-page-title-main">P2Y receptor</span> Subclass of purinergic P2 receptors

P2Y receptors are a family of purinergic G protein-coupled receptors, stimulated by nucleotides such as adenosine triphosphate, adenosine diphosphate, uridine triphosphate, uridine diphosphate and UDP-glucose.To date, 8 P2Y receptors have been cloned in humans: P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13 and P2Y14.

<span class="mw-page-title-main">Ectonucleotidase</span>

Ectonucleotidases consist of families of nucleotide metabolizing enzymes that are expressed on the plasma membrane and have externally oriented active sites. These enzymes metabolize nucleotides to nucleosides. The contribution of ectonucleotidases in the modulation of purinergic signaling depends on the availability and preference of substrates and on cell and tissue distribution.

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<span class="mw-page-title-main">P2RX7</span> Protein-coding gene in the species Homo sapiens

P2X purinoceptor 7 is a protein that in humans is encoded by the P2RX7 gene.

<span class="mw-page-title-main">P2RY1</span> Protein-coding gene in the species Homo sapiens

P2Y purinoceptor 1 is a protein that in humans is encoded by the P2RY1 gene.

<span class="mw-page-title-main">P2RY2</span> Protein-coding gene in the species Homo sapiens

P2Y purinoceptor 2 is a protein that in humans is encoded by the P2RY2 gene.

P2 receptor may refer to:

<span class="mw-page-title-main">P2RX4</span> Protein-coding gene in the species Homo sapiens

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

<span class="mw-page-title-main">P2RX5</span> Protein-coding gene in the species Homo sapiens

P2X purinoceptor 5 is a protein that in humans is encoded by the P2RX5 gene.

<span class="mw-page-title-main">P2RX3</span> Protein-coding gene in the species Homo sapiens

P2X purinoceptor 3 is a protein that in humans is encoded by the P2RX3 gene.

<span class="mw-page-title-main">Rostral ventromedial medulla</span> Group of neurons in medulla of brain

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<span class="mw-page-title-main">Purinergic signalling</span> Signalling complex involving purine nucleosides and their receptors

Purinergic signalling is a form of extracellular signalling mediated by purine nucleotides and nucleosides such as adenosine and ATP. It involves the activation of purinergic receptors in the cell and/or in nearby cells, thereby regulating cellular functions.

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References

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  2. 1 2 3 4 Burnstock, G. (2013). "Introduction to Purinergic Signalling in the Brain". Glioma Signaling. Advances in Experimental Medicine and Biology. Vol. 986. pp. 1–12. doi:10.1007/978-94-007-4719-7_1. ISBN   978-94-007-4718-0. PMID   22879061.
  3. ↑ Ulrich H, Abbracchio MP, Burnstock G (Sep 2012). "Extrinsic purinergic regulation of neural stem/progenitor cells: implications for CNS development and repair". Stem Cell Reviews. 8 (3): 755–67. doi:10.1007/s12015-012-9372-9. PMID   22544361. S2CID   10616782.
  4. ↑ King BF, Burnstock G (2002) Purinergic receptors. In: Pangalos M, Davies C (eds) Understanding G protein-coupled receptors and their role in the CNS. Oxford University Press, Oxford, pp 422– 438
  5. ↑ Cao Y, Tanaka K, Nguyen CT, Stacey G (Aug 2014). "Extracellular ATP is a central signaling molecule in plant stress responses". Current Opinion in Plant Biology. 20: 82–7. doi:10.1016/j.pbi.2014.04.009. PMID   24865948.
  6. ↑ Kaczmarek-Hájek K, Lörinczi E, Hausmann R, Nicke A (Sep 2012). "Molecular and functional properties of P2X receptors--recent progress and persisting challenges". Purinergic Signalling. 8 (3): 375–417. doi:10.1007/s11302-012-9314-7. PMC   3360091 . PMID   22547202.
  7. ↑ Burnstock G, Fredholm BB, North RA, Verkhratsky A (Jun 2010). "The birth and postnatal development of purinergic signalling". Acta Physiologica. 199 (2): 93–147. doi:10.1111/j.1748-1716.2010.02114.x. PMID   20345419. S2CID   25734771.
  8. ↑ Acuña-Castillo, Claudio; Morales, Bernardo; Huidobro-Toro, J. Pablo (2002-01-18). "Zinc and Copper Modulate Differentially the P2X4 Receptor". Journal of Neurochemistry. 74 (4): 1529–1537. doi: 10.1046/j.1471-4159.2000.0741529.x . PMID   10737610. S2CID   19142246.
  9. ↑ Zemkova, Hana (January 2021). "Special Issue of International Journal of Molecular Sciences (IJMS) "Purinergic P2 Receptors: Structure and Function"". International Journal of Molecular Sciences. 22 (1): 383. doi: 10.3390/ijms22010383 . PMID   33396540.
  10. ↑ Neuroscience. 2nd edition. Purves D, Augustine GJ, Fitzpatrick D, et al., editors. Sunderland (MA): Sinauer Associates; 2001.
  11. ↑ Jarvis MF (2010). "The neural–glial purinergic receptor ensemble in chronic pain states". Trends Neurosci. 33 (1): 48–57. doi:10.1016/j.tins.2009.10.003. PMID   19914722. S2CID   26035589.
  12. ↑ Tsuda M, Kuboyama K, Inoue T, Nagata K, Tozaki-Saitoh H, Inoue K (2009). "Behavioral phenotypes of mice lacking purinergic P2X4 receptors in acute and chronic pain assays". Molecular Pain. 5: 1744–8069–5–28. doi:10.1186/1744-8069-5-28. PMC   2704200 . PMID   19515262.
  13. ↑ Ulmann L, Hirbec H, Rassendren F (Jul 2010). "P2X4 receptors mediate PGE2 release by tissue-resident macrophages and initiate inflammatory pain". The EMBO Journal. 29 (14): 2290–300. doi:10.1038/emboj.2010.126. PMC   2910276 . PMID   20562826.
  14. ↑ Tsuda M, Shigemoto-Mogami Y, Koizumi S, Mizokoshi A, Kohsaka S, Salter MW, Inoue K (Aug 2003). "P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury". Nature. 424 (6950): 778–83. doi:10.1038/nature01786. PMID   12917686. S2CID   4358793.
  15. ↑ Kobayashi K, Takahashi E, Miyagawa Y, Yamanaka H, Noguchi K (Oct 2011). "Induction of the P2X7 receptor in spinal microglia in a neuropathic pain model". Neuroscience Letters. 504 (1): 57–61. doi:10.1016/j.neulet.2011.08.058. PMID   21924325. S2CID   32284927.
  16. ↑ Chessell IP, Hatcher JP, Bountra C, Michel AD, Hughes JP, Green P, Egerton J, Murfin M, Richardson J, Peck WL, Grahames CB, Casula MA, Yiangou Y, Birch R, Anand P, Buell GN (Apr 2005). "Disruption of the P2X7 purinoceptor gene abolishes chronic inflammatory and neuropathic pain". Pain. 114 (3): 386–96. doi:10.1016/j.pain.2005.01.002. PMID   15777864. S2CID   21486673.
  17. ↑ Zheng W, Watts LT, Holstein DM, Prajapati SI, Keller C, et al. (2010). "Purinergic Receptor Stimulation Reduces Cytotoxic Edema and Brain Infarcts in Mouse Induced by Photothrombosis by Energizing Glial Mitochondria". PLOS ONE. 5 (12): e14401. doi: 10.1371/journal.pone.0014401 . PMC   3008710 . PMID   21203502.
  18. ↑ Solini A, Chiozzi P, Falzoni S, Morelli A, Fellin R, Di Virgilio F (Oct 2000). "High glucose modulates P2X7 receptor-mediated function in human primary fibroblasts". Diabetologia. 43 (10): 1248–56. doi: 10.1007/s001250051520 . PMID   11079743.
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