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

Geoff Burnstock originally separated purinoceptors into P1 adenosine receptors and P2 nucleotide (ATP, ADP) receptors. [4] P2 receptors were later subdivided into P2X, P2Y, P2T, and P2Z receptors. [5] Subclasses X and Y mediated vasoconstriction and vasodilation, respectively, in the smooth muscle of some arteries. They had been observed in blood vessels, smooth muscle, heart, hepatocytes, and parotid acinar cells. Subclass T was only observed in thrombocytes, platelets and megakaryocytes. Subclass Z required ~100 μM-ATP for activation, where the previous classes required <1 μM. They had been observed in mast cells and lymphocytes.

In the early 1990s, purinoceptors were cloned and characterized, and the P2 subclasses were redefined. [4] Now, P2 receptors are classified based on structure: P2X are ionotropic and P2Y are metabotropic. Appropriately, P2Z was reclassified as P2X7 [6] and P2T was reclassified as P2Y1. [7]

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.

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. [8] 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] [9] 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. [10] [11]

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. [12]

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. [13]

Recent research has identified a role for microglial P2X receptors in neuropathic pain and inflammatory pain, especially the P2X4 and P2X7 receptors. [14] [15] [16] [17] [18]

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. [19]

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. [20]

See also

Related Research Articles

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

The P2X receptors, also ATP-gated P2X receptor cation channel 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> Cells covering neuron soma in PNS ganglia

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.

<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">P2RX1</span> Protein-coding gene in the species Homo sapiens

P2X purinoceptor 1, also ATP receptor, is a protein that in humans is encoded by the P2RX1 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.

<span class="mw-page-title-main">P2RY11</span> Protein-coding gene in the species Homo sapiens

P2Y purinoceptor 11 is a protein that in humans is encoded by the P2RY11 gene.

<span class="mw-page-title-main">P2RY14</span> Protein-coding gene in the species Homo sapiens

P2Y purinoceptor 14 is a protein that in humans is encoded by the P2RY14 gene.

<span class="mw-page-title-main">P2RY10</span> Protein-coding gene in the species Homo sapiens

Putative P2Y purinoceptor 10 is a protein that, in humans, is encoded by the P2RY10 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. P2X purinoceptor 4 is a member of the P2X receptor family. P2X receptors are trimeric protein complexes that can be homomeric or heteromeric. These receptors are ligand-gated cation channels that open in response to ATP binding. Each receptor subtype, determined by the subunit composition, varies in its affinity to ATP and desensitization kinetics.

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

P2X purinoceptor 5 is a protein in humans that 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">P2RX6</span> Protein-coding gene in the species Homo sapiens

P2X purinoceptor 6 is a protein that in humans is encoded by the P2RX6 gene.

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

The rostral ventromedial medulla (RVM), or ventromedial nucleus of the spinal cord, is a group of neurons located close to the midline on the floor of the medulla oblongata. The rostral ventromedial medulla sends descending inhibitory and excitatory fibers to the dorsal horn spinal cord neurons. There are 3 categories of neurons in the RVM: on-cells, off-cells, and neutral cells. They are characterized by their response to nociceptive input. Off-cells show a transitory decrease in firing rate right before a nociceptive reflex, and are theorized to be inhibitory. Activation of off-cells, either by morphine or by any other means, results in antinociception. On-cells show a burst of activity immediately preceding nociceptive input, and are theorized to be contributing to the excitatory drive. Neutral cells show no response to nociceptive input.

<span class="mw-page-title-main">PPADS</span> Chemical compound

PPADS (pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid) is a selective purinergic P2X antagonist. It is able to block contractions of rabbit vas deferens induced by ATP or α,β,methylene-ATP. It appears to be relatively selective for P2X receptors, having no appreciable activity at α1 adrenergic, muscarinic M2 and M3, histamine H1, and adenosine A1 receptors.

<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.

Microglia are the primary immune cells of the central nervous system, similar to peripheral macrophages. They respond to pathogens and injury by changing morphology and migrating to the site of infection/injury, where they destroy pathogens and remove damaged cells.

References

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  7. ↑ Léon, Catherine; Hechler, Béatrice; Vial, Catherine; Leray, Claude; Cazenave, Jean-Pierre; Gachet, Christian (1997-02-10). "The P2Y 1 receptor is an ADP receptor antagonized by ATP and expressed in platelets and megakaryoblastic cells". FEBS Letters. 403 (1): 26–30. doi:10.1016/S0014-5793(97)00022-7. ISSN   0014-5793.
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  10. ↑ 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.
  11. ↑ 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 . PMC   7796286 . PMID   33396540.
  12. ↑ Neuroscience. 2nd edition. Purves D, Augustine GJ, Fitzpatrick D, et al., editors. Sunderland (MA): Sinauer Associates; 2001.
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  20. ↑ 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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