Understanding the Role of Adenosine A2AR Heteroreceptor Complexes in Neurodegeneration and Neuroinflammation (original) (raw)
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Adenosine A1 and A2A Receptors in the Brain: Current Research and Their Role in Neurodegeneration
Molecules
The inhibitory adenosine A1 receptor (A1R) and excitatory A2A receptor (A2AR) are predominantly expressed in the brain. Whereas the A2AR has been implicated in normal aging and enhancing neurotoxicity in multiple neurodegenerative diseases, the inhibitory A1R has traditionally been ascribed to have a neuroprotective function in various brain insults. This review provides a summary of the emerging role of prolonged A1R signaling and its potential cross-talk with A2AR in the cellular basis for increased neurotoxicity in neurodegenerative disorders. This A1R signaling enhances A2AR-mediated neurodegeneration, and provides a platform for future development of neuroprotective agents in stroke, Parkinson's disease and epilepsy. each adenosine receptor are known, the intracellular effects of their activation are wide ranging and may vary based on cell function and location. In the brain, A1, A2B, and A3 receptors have widespread distribution, although A2B and A3 receptors have relatively low levels. However, A2ARs are primarily localized in the striatum, olfactory tubercle, and the nucleus accumbens . In addition, these receptors have different affinities for adenosine, with the A1R having the highest affinity at approximately 70 nM and the A2AR having a lower affinity at approximately 150 nM . The A2B and A3 receptors have a much lower affinity at 5100 nM and 6500 nM, respectively . These affinities, along with differential expression of A1 and A2ARs in the brain, play a key role in these receptor actions in the brain.
Adenosine receptors and brain diseases: Neuroprotection and neurodegeneration
Biochimica et Biophysica Acta (BBA) - Biomembranes, 2011
Adenosine acts in parallel as a neuromodulator and as a homeostatic modulator in the central nervous system. Its neuromodulatory role relies on a balanced activation of inhibitory A 1 receptors (A1R) and facilitatory A 2A receptors (A2AR), mostly controlling excitatory glutamatergic synapses: A1R impose a tonic brake on excitatory transmission, whereas A2AR are selectively engaged to promote synaptic plasticity phenomena. This neuromodulatory role of adenosine is strikingly similar to the role of adenosine in the control of brain disorders; thus, A1R mostly act as a hurdle that needs to be overcame to begin neurodegeneration and, accordingly, A1R only effectively control neurodegeneration if activated in the temporal vicinity of brain insults; in contrast, the blockade of A2AR alleviates the long-term burden of brain disorders in different neurodegenerative conditions such as ischemia, epilepsy, Parkinson's or Alzheimer's disease and also seem to afford benefits in some psychiatric conditions. In spite of this qualitative agreement between neuromodulation and neuroprotection by A1R and A2AR, it is still unclear if the role of A1R and A2AR in the control of neuroprotection is mostly due to the control of glutamatergic transmission, or if it is instead due to the different homeostatic roles of these receptors related with the control of metabolism, of neuronglia communication, of neuroinflammation, of neurogenesis or of the control of action of growth factors. In spite of this current mechanistic uncertainty, it seems evident that targeting adenosine receptors might indeed constitute a novel strategy to control the demise of different neurological and psychiatric disorders. This article is part of a Special Issue entitled: "Adenosine Receptors".
Adenosine A2A receptors control neuroinflammation and consequent hippocampal neuronal dysfunction
Journal of Neurochemistry, 2011
Neurological diseases account for approximately 30% of the total disease burden in Europe and neurodegenerative diseases account for a significant proportion of these (Olesen and Leonardi 2003). The neuromodulation system operated by adenosine has received an increasing attention as a potential novel target to manage neurodegenerative conditions, in view of its combined neuronal, glial and vascular effects (reviewed in Fredholm et al. 2005). This is best exemplified by the current development (phase IIb) of adenosine A 2A receptor (A2AR) antagonists as anti-Parkin-
Adenosine: a prototherapeutic concept in neurodegeneration
1995
Ten years ago, Newby introduced a new description of adenosine: "the retaliatory metabolite."' The theoretical notion that adenosine may protect against tissue injury2 evolved rapidly into a practical demonstration of powerful neuroprotective effects of endogenous adenosine and its analogue^.^-^ Subsequent improvement in understanding both the effects of adenosine receptor stimulation and the pathological processes that accompany numerous neurological disorders ultimately led to proposals that adenosine-based therapies may be effective not only in stroke and seizures, but also in Alzheimer's, Huntington's and Parkinson's diseases, and a number of psychiatric ADENOSINE AND BRAIN: THE FUNCTIONS Endogenous Brain Adenosine and Pathologic Stress Technical difficulties complicate the exact measurement of extracellular brain adenosine c~ncentration.~ Currently, the level of free adenosine level in the interstitial brain space ol' unanesthetized, freely moving animals is estimated at 50-300 nM.4 More importantly, however, several laboratories have consistently reported that the amount of extracellular adenosine increases dramatically following cerebral metabolic stress caused by seizures, hypoxia, or i~c h e m i a .~ In focal ischemia (and probably global as well), the reduction of cerebral blood flow (CBF) correlates with the concomitant elevation of both adenosine and gluta-"DvL is a Special Fellow of the Cystic Fibrosis Foundation, Washington, DC, and of Gilead Sciences, Foster City, CA. 163 164 ANNALS NEW YORK ACADEMY OF SCIENCES mate.' However, while increased release of adenosine occurs at CBF values of 25 m1/100 g/min, further reduction of CBF (20 mlilOO gimin) is necessary to elevate concentration of the extracellular glutamate. Quite recently, Hoehn and showed that release of excitatory amino acids elicited by electrical field stimulation also results in the release of adenosine-an effect mediated in part by both Nmethyl-D-aspartate (NMDA) and e-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA) receptors. It appears, therefore, that glutamate-mediated hyperexcitation of neurons (such as seen in cerebral ischemia) may provide an additional, and somewhat unexpected, stimulus for further increase in adenosine release. These observations indicate that, in view of the powerful inhibitory effect of adenosine on the release of several excitatory neurotransmitters (see below), it is quite likely that increase in the concentration of interstitial adenosine, which both precedes and accompanies massive intraischemic release of gl~tamate,'"-'~ constitutes part of a mechanism whose operation provides a transient, endogenous protection of the brain against i n j~r y .~ Cerebral Receptors of Adenosine Endogenous adenosine acts at three principal G-protein-associated receptor subtypes: Al, A2 and A3.'4s1s Both the molecular structure and the nature of the effector coupling are known for all three subtype^.'^.'^ Cerebral A1 receptors are linked to several second messenger systems, and one of their characteristic responses to stimulation is inhibition of adenylate c y c l a~e. '~ Activation of A2 receptors stimulates adenylate c y c l a~e , '~ whereas activation of A3 receptors inhibits it, and also stimulates phosphoinositide metabolism. l 8 Although their specific distribution varies,I9 all three adenosine receptor subtypes are found in the brain.'5.20 Al receptors are predominantly found in the hippocampus, IV-VI laminas of the cortex, striatum, amygdala, and superior colliculus, and appear to be codistributed with NMDA receptors.21.22 A1 receptors, of which two subclasses (Aza and A26) exist, abound on smooth muscle and endothelial cells of cerebral blood vessels, where they mediate vascular effects of adenosine.23 High-affinity Aza receptors are particularly well represented in the striaturn and other dopamine-rich regions of the brain,I9 where they are colocalized with dopamine D2 receptors, and exert profound modulatory effect on dopaminergic t r a n s m i~s i o n .~~ Adenosine receptors on glial cells belong, most likely, to the low-affinity AZI , s~b c l a s s .~ Cerebral distribution of A1 and A2 receptors follows an intriguing pattern, i. e. , A2 appear to be less abundant within regions where the density of Al sites is elevated, and vice versa. Differences in the anatomical distribution of AI and A2 receptors may have striking behavioral consequences.25 A3 receptors are found throughout the brain but their density is much lower than that of either A1 or A2.20 The cell type on which they are located is unknown. Physiological Effects of Adenosine Receptor Stimulation The principal function of adenosine in the brain is that of an inhibitory neurom o d~l a t o r. '~.~~ The inhibitory effects of adenosine are mediated mainly via both pre-and postsynaptic A1 receptors.
Adenosine Receptors in Modulation of Central Nervous System Disorders
Current Pharmaceutical Design, 2019
The ubiquitous signaling nucleoside molecule, adenosine is found in different cells of the human body to provide its numerous pharmacological role. The associated actions of endogenous adenosine are largely dependent on conformational change of the widely expressed heterodimeric G-protein-coupled A1, A2A, A2B, and A3 adenosine receptors (ARs). These receptors are well conserved on the surface of specific cells, where potent neu-romodulatory properties of this bioactive molecule reflected by its easy passage through the rigid blood-brain-barrier, to simultaneously act on the Central Nervous System (CNS). The minimal concentration of adenosine in body fluids (30-300 nM) is adequate to exert its neuromodulatory action in the CNS, whereas the modulatory effect of adenosine on ARs is the consequence of several neurodegenerative diseases. Modulatory action concerning the activation of such receptors in the CNS could be facilitated towards neuroprotective action against such CNS disorders. Our aim herein is to discuss briefly pathophysiological roles of adenosine on ARs in the modulation of different CNS disorders, which could be focused towards the identification of potential drug targets in recovering accompanying CNS disorders. Researches with active components with AR modulatory action have been extended and already reached to the bedside of the patients through clinical research in the improvement of CNS disorders. Therefore, this review consist of recent findings in literatures concerning the impact of ARs on diverse CNS disease pathways with the possible relevance to neurodegeneration.
Recently evidence has been presented that adenosine A 2A and dopamine D 2 receptors form functional heteromeric receptor complexes as demonstrated in human neuroblastoma cells and mouse fibroblast Ltk Ϫ cells. These A 2A /D 2 heteromeric receptor complexes undergo coaggregation, cointernalization, and codesensitization on D 2 or A 2A receptor agonist treatments and especially after combined agonist treatment. It is hypothesized that the A 2A /D 2 receptor heteromer represents the molecular basis for the antagonistic A 2A /D 2 receptor interactions demonstrated at the biochemical and behavioral levels. Functional heteromeric complexes between A 2A and metabotropic glutamate 5 receptors (mGluR5) have also recently been demonstrated in HEK-293 cells and rat striatal membrane preparations. The A 2A /mGluR5 receptor heteromer may account for the synergism found after combined agonist treatments demonstrated in different in vitro and in vivo models. D 2 , A 2A , and mGluR5 receptors are found together in the dendritic spines of the striatopallidal GABA neurons. Therefore, possible D 2 /A 2A /mGluR5 multimeric receptor complexes and the receptor interactions within them may have a major role in controlling the dorsal and ventral striatopallidal GABA neurons involved in Parkinson's disease and in schizophrenia and drug addiction, respectively.
Progress in Neurobiology, 2007
This review summarizes recent developments that have contributed to understand how adenosine receptors, particularly A2A receptors, modulate brain injury in various animal models of neurological disorders, including Parkinson's disease (PD), stroke, Huntington's disease (HD), multiple sclerosis, Alzheimer's disease (AD) and HIV-associated dementia. It is clear that extracellular adenosine acting at adenosine receptors influences the functional outcome in a broad spectrum of brain injuries, indicating that A2A Rs may modulate some general cellular processes to affect neuronal cells death. Pharmacological, neurochemical and molecular/genetic approaches to the complex actions of A2A receptors in different cellular elements suggest that A2A receptor activation can be detrimental or protective after brain insults, depending on the nature of brain injury and associated pathological conditions. An interesting concept that emerges from these studies is A2A R's ability to fine tune neuronal and glial functions to produce neuroprotective effects. While the data presented here clearly highlight the complexity of using adenosinergic agents therapeutically in PD and other neurodegenerative disorders and point out many areas for further inquiry, they also confirm that adenosine receptor ligands, particularly A2A receptor ligands, have many promising characteristics that encourage the pursuit of their therapeutic potential.
Adenosine A1 receptor: Functional receptor-receptor interactions in the brain
Purinergic Signalling, 2007
Over the past decade, many lines of investigation have shown that receptor-mediated signaling exhibits greater diversity than previously appreciated. Signal diversity arises from numerous factors, which include the formation of receptor dimers and interplay between different receptors. Using adenosine A 1 receptors as a paradigm of G protein-coupled receptors, this review focuses on how receptor-receptor interactions may contribute to regulation of the synaptic transmission within the central nervous system. The interactions with metabotropic dopamine, adenosine A 2A , A 3 , neuropeptide Y, and purinergic P2Y 1 receptors will be described in the first part.