Adenosine receptor
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The adenosine receptors (or P1 receptors.
The adenosine receptors are commonly known for their antagonists caffeine, theobromine, and theophylline, whose action on the receptors produces the stimulating effects of coffee, tea and chocolate.
Pharmacology
Each type of adenosine receptor has different functions, although with some overlap. while the A2B and A3 receptors are located mainly peripherally and are involved in processes such as inflammation and immune responses.
Most older compounds acting on adenosine receptors are nonselective, with the endogenous agonist
Newer adenosine receptor agonists and antagonists are much more potent and subtype-selective, and have allowed extensive research into the effects of blocking or stimulating the individual adenosine receptor subtypes, which is now resulting in a new generation of more selective drugs with many potential medical uses. Some of these compounds are still derived from adenosine or from the xanthine family, but researchers in this area have also discovered many selective adenosine receptor ligands that are entirely structurally distinct, giving a wide range of possible directions for future research.[13][14]
Subtypes
Comparison
| Receptor | Gene | Mechanism [15] | Effects | Agonists | Antagonists |
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| A1 | ADORA1 | Gi/o → cAMP↑/↓
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| A2A | ADORA2A | Gs → cAMP↑ |
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| A2B | ADORA2B | Gs → cAMP↑
Also recently discovered A2B has Gq → myosin light chain kinase → phosphorylate myosin light chain → myosin light chain plus actin → bronchoconstriction[citation needed ]
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| A3 | ADORA3 | Gi/o → ↓cAMP |
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A1 adenosine receptor
The adenosine A1 receptor has been found to be ubiquitous throughout the entire body.
Mechanism
This receptor has an inhibitory function on most of the tissues in which it is expressed. In the brain, it slows metabolic activity by a combination of actions. Presynaptically, it reduces synaptic vesicle release while post synaptically it has been found to stabilize the magnesium on the NMDA receptor.
Antagonism and agonism
Specific A1
Tecadenoson is an effective A1 adenosine agonist, as is selodenoson.
In the heart
The A1, together with A2A receptors of endogenous adenosine play a role in regulating
In normal physiological states, this serves as a protective mechanism. However, in altered cardiac function, such as
In neonatal medicine
Adenosine antagonists are widely used in
A reduction in A1 expression appears to prevent hypoxia-induced ventriculomegaly and loss of white matter, which raises the possibility that pharmacological blockade of A1 may have clinical utility.
Theophylline and caffeine are nonselective adenosine antagonists that are used to stimulate respiration in premature infants.
Bone homeostasis
Adenosine receptors play a key role in the homeostasis of bone. The A1 receptor has been shown to stimulate osteoclast differentiation and function.[17] Studies have found that blockade of the A1 Receptor suppresses the osteoclast function, leading to increased bone density.[18]
A2A adenosine receptor
As with the A1, the A2A receptors are believed to play a role in regulating myocardial oxygen consumption and coronary blood flow.
Mechanism
The activity of A2A adenosine receptor, a G-protein coupled receptor family member, is mediated by G proteins that activate adenylyl cyclase. It is abundant in basal ganglia, vasculature and platelets and it is a major target of caffeine.[19]
Function
The A2A receptor is responsible for regulating myocardial blood flow by
Agonists and antagonists
Specific antagonists include istradefylline (KW-6002) and SCH-58261, while specific agonists include CGS-21680 and ATL-146e.[20]
Bone homeostasis
The role of A2A receptor opposes that of A1 in that it inhibits osteoclast differentiation and activates osteoblasts.[21] Studies have shown it to be effective in decreasing inflammatory osteolysis in inflamed bone.[22] This role could potentiate new therapeutic treatment in aid of bone regeneration and increasing bone volume.
A2B adenosine receptor
This integral membrane protein stimulates adenylate cyclase activity in the presence of adenosine. This protein also interacts with
Bone homeostasis
Similarly to A2A receptor, the A2B receptor promotes osteoblast differentiation.[23] The osteoblast cell is derived from the Mesenchymal Stem Cell (MSC) which can also differentiate into a chondrocyte.[24] The cell signalling involved in the stimulation of the A2B receptor directs the route of differentiation to osteoblast, rather than chondrocyte via the Runx2 gene expression.[24] Potential therapeutic application in aiding bone degenerative diseases, age related changes as well as injury repair.
A3 adenosine receptor
It has been shown in studies to inhibit some specific signal pathways of adenosine. It allows for the inhibition of growth in human melanoma cells. Specific antagonists include MRS1191, MRS1523 and MRE3008F20, while specific agonists include
Bone homeostasis
The role of A3 receptor is less defined in this field. Studies have shown that it plays a role in the downregulation of osteoclasts.[25] Its function in regards to osteoblasts remains ambiguous.
References
- PMID 9133776.
- PMID 11734617.
- PMID 17874974.
- PMID 18160539.
- PMID 16806272.
- PMID 17572452.
- PMID 17646043.
- PMID 18537674.
- PMID 17408751.
- PMID 17999026.
- PMID 18088379.
- PMID 17373584.
- PMID 18181659.
- PMID 18537675.
- ^ Unless else specified in boxes, then ref is:senselab Archived 2009-02-28 at the Wayback Machine
- ISBN 978-0071794763. Retrieved 30 March 2024.
- ^ Kara FM, Doty SB, Boskey A, Goldring S.. (2010). Adenosine A1 Receptors (A1R) Regulate Bone Resorption II Adenosine A1R Blockade or Deletion Increases Bone Density and Prevents Ovariectomy-Induced Bone Loss. Arthritis Rheumatology . 62 (2), 534–541.
- PMC 3838692.
- ^ "Entrez Gene: ADORA2A adenosine A2A receptor".
- ^ PMID 16518376.
- ^ Mediero A, Frenkel SR, Wilder T, HeW MA, Cronstein BN (2012). "Adenosine A2A receptor activation prevents wearparticle-induced osteolysis". Sci Transl Med. 4 (135): 135–165.
- PMC 3349861.
- .
- ^ .
- ^ Rath-Wolfson L, Bar-Yehuda S, Madi L, Ochaion A, Cohen S, Zabutti A, Fishman P (2006). "IB-MECA, an A". Clin Exp Rheumatol. 24: 400–406.
External links
- "Adenosine Receptors". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from the original on 2016-10-24. Retrieved 2006-07-20.
- Adenosine+Receptors at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
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