Purinergic receptor
Purinergic receptors, also known as purinoceptors, are a family of plasma membrane molecules involved in several cellular functions such as vascular reactivity, apoptosis and cytokine secretion. These functions have not been well characterized and the effect of the extracellular microenvironment on their function is also poorly understood. 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 them further, the subclasses have been divided into families of metabotropic (P2Y, P2U, and P2T) and ionotropic receptors (P2X and P2Z).[1]
These receptors have their effect of high glucose concentration on ATP-mediated responses in human fibroblasts.
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[edit] 3 Classes of Purinergic Receptors
| Name | Activation | Class |
| 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.
[edit] P2X receptors
P2X receptors are associated with ligand-gated ion channels, whereas the P1 and P2Y receptors are G protein-coupled metabotropic receptors. The ligand-gated ion channels are nonselective cation channels responsible for mediating excitatory postsynaptic responses, behaving in a similar nature to nicotinic and ionotropic glutamate receptors. P2X receptors are distinct from the rest of the widely known ligand-gated ion channels, as the genetic encoding of these particular channels suggest a unique subunit arrangement, indicating the presence of only two transmembrane domains within the channels. These receptors are greatly distributed in central and peripheral neurons. Regarding sensory neurons, there is evidence to suggest that P2X receptors play a role in mechanosensation and pain. Their specific role beyond sensory neurons is widely unknown.[2]
[edit] 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.[3]
[edit] Inhibitors
Inhibitors of purinergic receptors include clopidogrel, prasugrel and ticlopidine, as well as ticagrelor. All of these are antiplatelet agents that block P2Y12 receptors.
[edit] 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, and that ATP acts 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.[4]
[edit] Effects on Cytotoxic Edema
Purinergic receptors have been suggested to play a role in the treatment of cytotoxic edema and 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 a 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 cytoxic 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.[5]
[edit] References
- ^ 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
- ^ Neuroscience. 2nd edition. Purves D, Augustine GJ, Fitzpatrick D, et al., editors. Sunderland (MA): Sinauer Associates; 2001.
- ^ Neuroscience. 2nd edition. Purves D, Augustine GJ, Fitzpatrick D, et al., editors. Sunderland (MA): Sinauer Associates; 2001.
- ^ M.F. Jarvis The neural–glial purinergic receptor ensemble in chronic pain states Trends Neurosci., 33 (2010), pp. 48–57
- ^ 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.00144
[edit] External links
- IUPHAR GPCR Database - Adenosine receptors
- IUPHAR GPCR Database - P2Y receptors
- Purinergic+Receptors at the US National Library of Medicine Medical Subject Headings (MeSH)
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