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1.
腺苷作为神经调质,调节多种神经生物学功能.随觉醒时间延长,动物脑内腺苷水平逐渐增高,在睡眠期显著降低.因此,腺苷被认为是调节睡眠的内稳态因子之一.腺苷受体(receptor,R)有A1R、A2AR、A2BR和A3R四种亚型,其中A1R和A2AR与诱导睡眠相关.激活A1R可抑制促觉醒神经元诱导睡眠,也可抑制促眠神经元导致... 相似文献
2.
Adenosine is an important regulatory metabolite and an inhibitor of platelet activation. Adenosine released from different
cells or generated through the activity of cell-surface ectoenzymes exerts its effects through the binding of four different
G-protein-coupled adenosine receptors. In platelets, binding of A 2 subtypes (A 2A or A 2B) leads to consequent elevation of intracellular cyclic adenosine monophosphate, an inhibitor of platelet activation. The
significance of this ligand and its receptors for platelet activation is addressed in this review, including how adenosine
metabolism and its A 2 subtype receptors impact the expression and activity of adenosine diphosphate receptors. The expression of A 2 adenosine receptors is induced by conditions such as oxidative stress, a hallmark of aging. The effect of adenosine receptors
on platelet activation during aging is also discussed, as well as potential therapeutic applications. 相似文献
3.
Adenosine modulates many aspects of human physiology and pathophysiology through binding to the adenosine family of G protein-coupled receptors, which are comprised of four subtypes, the A 1R, A 2AR, A 2BR and A 3R. Modulation of adenosine receptor function by exogenous agonists, antagonists and allosteric modulators can be beneficial for a number of conditions including cardiovascular disease, Parkinson's disease, and cancer. Unfortunately, many preclinical drug candidates targeting adenosine receptors have failed in clinical trials due to limited efficacy and/or severe on-target undesired effects. To overcome the key barriers typically encountered when transitioning adenosine receptor ligands into the clinic, research efforts have focussed on exploiting the phenomenon of biased agonism. Biased agonism provides the opportunity to develop ligands that favour therapeutic signalling pathways, whilst avoiding signalling associated with on-target undesired effects. Recent studies have begun to define the structure-function relationships that underpin adenosine receptor biased agonism and establish how this phenomenon can be harnessed therapeutically. In this review we describe the recent advancements made towards achieving therapeutically relevant biased agonism at adenosine receptors. 相似文献
4.
Adenosine A 1 and A 2A receptors are attracting great interest as drug targets for their role in cognitive and motor deficits, respectively. Antagonism of both these adenosine receptors may offer therapeutic benefits in complex neurological diseases, such as Alzheimer’s and Parkinson’s disease. The aim of this study was to explore the affinity and selectivity of 2-benzylidene-1-tetralone derivatives as adenosine A 1 and A 2A receptor antagonists. Several 5-hydroxy substituted 2-benzylidene-1-tetralone analogues with substituents on ring B were synthesized and assessed as antagonists of the adenosine A 1 and A 2A receptors via radioligand binding assays. The results indicated that hydroxy substitution in the meta and para position of phenyl ring B, displayed the highest selectivity and affinity for the adenosine A 1 receptor with K i values in the low micromolar range. Replacement of ring B with a 2-amino-pyrimidine moiety led to compound 12 with an increase of affinity and selectivity for the adenosine A 2A receptor. These substitution patterns led to enhanced adenosine A 1 and A 2A receptor binding affinity. The para-substituted 5-hydroxy analogue 3 behaved as an adenosine A 1 receptor antagonists in a GTP shift assay performed with rat whole brain membranes expressing adenosine A 1 receptors. In conclusion, compounds 3 and 12, showed the best adenosine A 1 and A 2A receptor affinity respectively, and therefore represent novel adenosine receptor antagonists that may have potential with further structural modifications as drug candidates for neurological disorders. 相似文献
5.
Adenosine plays an important role in regulating intestinal motility and inflammatory processes. Previous studies in rodent models have demonstrated that adenosine metabolism and signalling are altered during chronic intestinal inflammatory diseases. However, the involvement of the adenosinergic system in the pathophysiology of gut dysmotility associated to a primary neurodysfunction is still unclear. Recently, we showed that the neurotropic Herpes simplex virus type-1 (HSV-1), orally inoculated to rodents, infects the rat enteric nervous system (ENS) and affects gut motor function without signs of systemic infection. In this study we examined whether changes in purinergic metabolism and signaling occur during permanent HSV-1 infection of rat ENS. Using isolated organ bath assays, we found that contraction mediated by adenosine engagement of A 1 or A 2A receptors was impaired at 1 and 6 weeks post-viral administration. Immunofluorescence studies revealed that viral infection of ENS led to a marked redistribution of adenosine receptors: A 1 and A 2B receptors were confined to the muscle layers whereas A 2A and A 3 receptors were expressed mainly in the myenteric plexus. Viral-induced ENS neurodysfunction influenced adenosine metabolism by increasing adenosine deaminase and CD73 levels in longitudinal muscle-myenteric plexus with no sign of frank inflammation. This study provides the first evidence for involvement of the adenosinergic system during HSV-1 infection of the ENS. As such, this may represent a valid therapeutic target for modulating gut contractility associated to a primary neurodysfunction. 相似文献
6.
D 1- and D 2-types of dopamine receptors are located separately in direct and indirect pathway striatal projection neurons (dSPNs and iSPNs). In comparison, adenosine A 1-type receptors are located in both neuron classes, and adenosine A 2A-type receptors show a preferential expression in iSPNs. Due to their importance for neuronal excitability, Ca 2+-currents have been used as final effectors to see the function of signaling cascades associated with different G protein-coupled receptors. For example, among many other actions, D 1-type receptors increase, while D 2-type receptors decrease neuronal excitability by either enhancing or reducing, respectively, Ca V1 Ca 2+-currents. These actions occur separately in dSPNs and iSPNs. In the case of purinergic signaling, the actions of A 1- and A 2A-receptors have not been compared observing their actions on Ca 2+-channels of SPNs as final effectors. Our hypotheses are that modulation of Ca 2+-currents by A 1-receptors occurs in both dSPNs and iSPNs. In contrast, iSPNs would exhibit modulation by both A 1- and A 2A-receptors. We demonstrate that A 1-type receptors reduced Ca 2+-currents in all SPNs tested. However, A 2A-type receptors enhanced Ca 2+-currents only in half tested neurons. Intriguingly, to observe the actions of A 2A-type receptors, occupation of A 1-type receptors had to occur first. However, A 1-receptors decreased Ca V2 Ca 2+-currents, while A 2A-type receptors enhanced current through Ca V1 channels. Because these channels have opposing actions on cell discharge, these differences explain in part why iSPNs may be more excitable than dSPNs. It is demonstrated that intrinsic voltage-gated currents expressed in SPNs are effectors of purinergic signaling that therefore play a role in excitability. 相似文献
7.
BackgroundGlaucoma, a leading cause of blindness worldwide, is an optic neuropathy commonly associated with elevated intraocular pressure (IOP). The major goals of glaucoma treatments are to lower IOP and protect retinal ganglion cells. It has been revealed recently that adenosine and adenosine receptors (ARs) have important roles in IOP modulation and neuroprotection. Scope of reviewThis article reviews recent studies on the important roles of adenosine and ARs in aqueous humor formation and outflow facility, IOP and retinal neuroprotection. Major conclusionsAdenosine and several adenosine derivatives increase and/or decrease IOP via A 2A AR. Activation of A 1 AR can reduce outflow resistance and thereby lower IOP, A 3 receptor antagonists prevent adenosine-induced activation of Cl − channels of the ciliary non-pigmented epithelial cells and thereby lower IOP. A 1 and A 2A agonists can reduce vascular resistance and increase retina and optic nerve head blood flow. A 1 agonist and A 2A antagonist can enhance the recovery of retinal function after ischemia attack. Adenosine acting at A 3 receptors can attenuate the rise in calcium and retinal ganglion cells death accompanying P2X(7) receptor activation. General significanceEvidence suggested that the adenosine system is one of the potential target systems for therapeutic approaches in glaucoma. 相似文献
8.
Pain is a common clinical symptom that seriously affects the quality of life in a variety of patient populations. In recent years, research on the role of adenosine signaling in pain modulation has made great progress. Adenosine is a purine nucleoside and a neuromodulator, and regulates multiple physiological and pathophysiological functions through the activation of four G protein–coupled receptors, which are classified as A 1, A 2A, A 2B, and A 3 adenosine receptors (ARs). Adenosine and its receptors that are widespread in the central nervous system (CNS) play an important role in the processing of nociceptive sensory signals in different pain models. A 1Rs have the highest affinity to adenosine, and the role in analgesia has been well investigated. The roles of A 2ARs and A 2BRs in the modulation of pain are controversial because they have both analgesic and pronociceptive effects. The analgesic effects of A 3Rs are primarily manifested in neuropathic pain. In this article, we have reviewed the recent studies on ARs in the modulation of neuropathic pain, inflammatory pain, postoperative pain, and visceral pain in the CNS. Furthermore, we have outlined the pathways through which ARs contribute to pain regulation, thereby shedding light on how this mechanism can be targeted to provide effective pain relief. 相似文献
9.
Adenosine plays a dual role on acetylcholine (ACh) release from myenteric motoneurons via the activation of high-affinity inhibitory A 1 and facilitatory A 2A receptors. The therapeutic potential of adenosine-related compounds for controlling intestinal motility and inflammation, prompted us to investigate further the role of low-affinity adenosine receptors, A 2B and A 3, on electrically-evoked (5 Hz, 200 pulses) [ 3H]ACh release from myenteric neurons. Immunolocalization studies showed that A 2B receptors exhibit a pattern of distribution similar to the glial cell marker, GFAP. Regarding A 1 and A 3 receptors, they are mainly distributed to cell bodies of ganglionic myenteric neurons, whereas A 2A receptors are localized predominantly on cholinergic nerve terminals. Using selective antagonists (DPCPX, ZM241385 and MRS1191), data indicate that modulation of evoked [ 3H]ACh release is balanced through tonic activation of inhibitory (A 1) and facilitatory (A 2A and A 3) receptors by endogenous adenosine. The selective A 2B receptor antagonist, PSB603, alone was devoid of effect and failed to modify the inhibitory effect of NECA. The A 3 receptor agonist, 2-Cl-IB MECA (1–10 nM), concentration-dependently increased the release of [ 3H]ACh. The effect of 2-Cl-IB MECA was attenuated by MRS1191 and by ZM241385, which selectively block respectively A 3 and A 2A receptors. In contrast to 2-Cl-IB MECA, activation of A 2A receptors with CGS21680C attenuated nicotinic facilitation of ACh release induced by focal depolarization of myenteric nerve terminals in the presence of tetrodotoxin. Tandem localization of excitatory A 3 and A 2A receptors along myenteric neurons explains why stimulation of A 3 receptors (with 2-Cl-IB MECA) on nerve cell bodies acts cooperatively with prejunctional facilitatory A 2A receptors to up-regulate acetylcholine release. The results presented herein consolidate and expand the current understanding of adenosine receptor distribution and function in the myenteric plexus of the rat ileum, and should be taken into consideration for data interpretation regarding the pathophysiological implications of adenosine on intestinal motility disorders. 相似文献
10.
The early stages of diabetic retinopathy (DR) are characterized by alterations similar to neurodegenerative and inflammatory conditions such as increased neural apoptosis, microglial cell activation and amplified production of pro-inflammatory cytokines. Adenosine regulates several physiological functions by stimulating four subtypes of receptors, A 1AR, A 2AAR, A 2BAR, and A 3AR. Although the adenosinergic signaling system is affected by diabetes in several tissues, it is unknown whether diabetic conditions in the retina can also affect it. Adenosine delivers potent suppressive effects on virtually all cells of the immune system, but its potential role in the context of DR has yet to be studied in full. In this study, we used primary mixed cultures of rat retinal cells exposed to high glucose conditions, to mimic hyperglycemia, and a streptozotocin rat model of type 1 diabetes to determine the effect diabetes/hyperglycemia have on the expression and protein levels of adenosine receptors and of the enzymes adenosine deaminase and adenosine kinase. We found elevated mRNA and protein levels of A 1AR and A 2AAR, in retinal cell cultures under high glucose conditions and a transient increase in the levels of the same receptors in diabetic retinas. Adenosine deaminase and adenosine kinase expression and protein levels showed a significant decrease in diabetic retinas 30 days after diabetes induction. An enzymatic assay performed in retinal cell cultures revealed a marked decrease in the activity of adenosine deaminase under high glucose conditions. We also found an increase in extracellular adenosine levels accompanied by a decrease in intracellular levels when retinal cells were subjected to high glucose conditions. In conclusion, this study shows that several components of the retinal adenosinergic system are affected by diabetes and high glucose conditions, and the modulation observed may uncover a possible mechanism for the alleviation of the inflammatory and excitotoxic conditions observed in diabetic retinas. 相似文献
11.
BackgroundAdenosine is generated in response to cellular stress and damage and is elevated in the lungs of patients with chronic lung disease. Adenosine signaling through its cell surface receptors serves as an amplifier of chronic lung disorders, suggesting adenosine-based therapeutics may be beneficial in the treatment of lung diseases such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Previous studies in mouse models of chronic lung disease demonstrate that the key components of adenosine metabolism and signaling are altered. Changes include an up-regulation of CD73, the major enzyme of adenosine production and down-regulation of adenosine deaminase (ADA), the major enzyme for adenosine metabolism. In addition, adenosine receptors are elevated. Methodology/Principal FindingsThe focus of this study was to utilize tissues from patients with COPD or IPF to examine whether changes in purinergic metabolism and signaling occur in human disease. Results demonstrate that the levels of CD73 and A 2BR are elevated in surgical lung biopsies from severe COPD and IPF patients. Immunolocalization assays revealed abundant expression of CD73 and the A 2BR in alternatively activated macrophages in both COPD and IPF samples. In addition, mediators that are regulated by the A 2BR, such as IL-6, IL-8 and osteopontin were elevated in these samples and activation of the A 2BR on cells isolated from the airways of COPD and IPF patients was shown to directly induce the production of these mediators. Conclusions/SignificanceThese findings suggest that components of adenosine metabolism and signaling are altered in a manner that promotes adenosine production and signaling in the lungs of patients with COPD and IPF, and provide proof of concept information that these disorders may benefit from adenosine-based therapeutics. Furthermore, this study provides the first evidence that A 2BR signaling can promote the production of inflammatory and fibrotic mediators in patients with these disorders. 相似文献
12.
Inosine is an endogenous purine nucleoside, which is formed during the breakdown of adenosine. The adenosinergic system was already described as capable of modulating mood in preclinical models; we now explored the effects of inosine in two predictive models of depression: the forced swim test (FST) and tail suspension test (TST). Mice treated with inosine displayed higher anti-immobility in the FST (5 and 50 mg/kg, intraperitoneal route (i.p.)) and in the TST (1 and 10 mg/kg, i.p.) when compared to vehicle-treated groups. These antidepressant-like effects started 30 min and lasted for 2 h after intraperitoneal administration of inosine and were not accompanied by any changes in the ambulatory activity in the open-field test. Both adenosine A 1 and A 2A receptor antagonists prevented the antidepressant-like effect of inosine in the FST. In addition, the administration of an adenosine deaminase inhibitor (1 and 10 mg/kg, i.p.) also caused an antidepressant-like effect in the FST. These results indicate that inosine possesses an antidepressant-like effect in the FST and TST probably through the activation of adenosine A 1 and A 2A receptors, further reinforcing the potential of targeting the purinergic system to the management of mood disorders. 相似文献
13.
Adenosine is an important mediator of inhibition of platelet activation. This metabolite is released from various cells, as well as generated via activity of ecto‐enzymes on the cell surface. Binding of adenosine to A 2 subtypes (A 2A or A 2B), G‐protein coupled adenosine receptors, results in increased levels of intracellular cyclic adenosine monophosphate (cAMP), a strong inhibitor of platelet activation. The role and importance of adenosine and its receptors in platelet physiology are addressed in this review, including recently identified roles for the A 2B adenosine receptor as a modulator of platelet activation through its newly described role in the control of expression of adenosine diphosphate (ADP) receptors. J. Cell. Physiol. 226: 46–51, 2010. © 2010 Wiley‐Liss, Inc. 相似文献
14.
G-protein-coupled receptors (GPCRs) are membrane proteins that have a wide variety of physiological roles. Adenosine receptors belong to the GPCR family. Adenosine receptors are implicated in many physiological disorders, such as Parkinson's disease, Huntington's disease, inflammatory and immune's disease and many others. Interestingly, crystal structures of the active and inactive conformations of the A 2-subtype adenosine receptor (A 2AR) have been solved. These two structures could be used to get insights about the conformational changes that occur during the process of activation/inactivation processes of this receptor. Therefore, two ligand-free simulations of the native active (PDB code: 3QAK) and inactive (PDB code: 3EML) conformations of the A 2AR and two halo-simulations were carried out to observe the initial conformational changes induced by coupling adenosine to the inactive conformation and caffeine to the active conformation. Furthermore, we constructed an A 2AR model that contained four thermostabilising mutations, L48A, T65A, Q89A and A54L, which had previously been determined to stabilise the bound conformation of the agonist, and we ran molecular dynamics simulations of this mutant to investigate how these point mutations might affect the inactive conformation of this receptor. This study provides insights about the initial structural and dynamic features that occur as a result of the binding of caffeine and adenosine in the active and inactive A 2AR structures, respectively, as well as the introduction of some mutations on the inactive structure of the A 2AR. Moreover, we provide useful and detailed information regarding structural features such as toggle switch and ionic lock during the activation/inactivation processes of this receptor. 相似文献
15.
Abstract Adenosine receptor agonists were shown to inhibit evoked release of the tachykinins Substance P and Neurokinin-A from perifused myenteric synaptosomes. The potencies of selective A 1 and A 2 agonists are consistent with activity at adenosine A 1 receptors located on the nerve endings. 相似文献
16.
Amyotrophic lateral sclerosis (ALS) is a fatal progressing neurodegenerative disease; to date, despite the intense research effort, only two therapeutic options, with very limited effects, are available. The purinergic system has been indicated as a possible new therapeutic target for ALS, but the results are often contradictory and generally confused. The present study was designed to determine whether P1 adenosine receptor ligands affected disease progression in a transgenic model of ALS. SOD1G93A mice were chronically treated, from presymptomatic stage, with a selective adenosine A2A receptor agonist (CGS21680), antagonist (KW6002) or the A1 receptor antagonist DPCPX. Body weight, motor performance and survival time were evaluated. The results showed that neither the stimulation nor the blockade of adenosine A2A receptors modified the progressive loss of motor skills or survival of mSOD1G93A mice. Conversely, blockade of adenosine A1 receptors from the presymptomatic stage significantly attenuated motor disease progression and induced a non-significant increase of median survival in ALS mice. Our data confirm that the modulation of adenosine receptors can elicit very different (and even opposite) effects during the progression of ALS course, thus strengthens the importance of further studies to elucidated their real therapeutic potential in this pathology. 相似文献
17.
There are four adenosine receptors, A 1, A 2A, A 2B and A 3, together forming a defined subgroup of G protein coupled receptors. They are well conserved and widely expressed. The endogenous agonist, adenosine, has a minimal concentration in body fluids (20-200 nM) that is sufficient to slightly activate the receptors where they are very highly expressed—as in the basal ganglia, on fat cells and in the kidney. Here adenosine can play a physiological role and here antagonists such as caffeine can have effects in healthy individuals. Adenosine levels rise in stress and distress (up to 30 μM in ischemia) and tend to minimize the risk for adverse outcomes by increasing energy supply and decreasing cellular work, by stimulating angiogenesis, mediating preconditioning and having multiple effects on immune competent cells. These pathophysiological roles of adenosine also offer some potential drug targets, but the fact that adenosine receptors are involved in so many processes does not simplify drug development. 相似文献
18.
BackgroundEssential hypertension is considered to be a multifactorial disorder and its aetiology has yet to be clearly identified. As the adenosine receptors have a significant role in mediating vasodilation, alterations in their structures or signalling pathways may be involved in the development of hypertension. This study aimed to measure the expression of adenosine A 3 receptors in a range of cardiovascular tissues and determine whether they could be altered with essential hypertension, and to functionally test responses to adenosine A 3 receptor agonists in coronary blood vessels using the isolated perfused heart preparation. MethodsmRNA samples from cardiovascular tissues and a range of blood vessels were collected from 10 week old male spontaneously hypertensive rats and age-gender matched Wistar rats (n = 8). The Langendorff heart perfusion preparation was used to characterise adenosine A 3 receptor mediated coronary vasodilation in the rat heart. ResultsAdenosine A 3 receptor agonists induced coronary vasodilation. The expression of adenosine A 3 receptors in cardiovascular tissues was altered in a tissue-specific pattern. Specifically, down-regulation of adenosine A 3 receptor expression occurred in hypertensive hearts, which might be associated with attenuated vasodilator responses observed in coronary vessels to adenosine A 3 receptor agonists. ConclusionsThis study demonstrated alterations in the expression of adenosine A 3 receptors occurred in a tissue specific mode, and reduced adenosine A 3 receptor mediated coronary vasodilation in hearts from spontaneously hypertensive rats. Our findings with regard to changes in the adenosine A 3 receptor in hypertensive hearts suggest that adenosine A 3 receptor might play a role in the physiopathology of essential hypertension and potentially open the way to pharmacologic manipulation of vasomotor activity by the use of adenosine A 3 receptor agonists. 相似文献
19.
Adenosine levels are increased in stress and act as anti-oxidant and anti-inflammatory mediators by binding to 4 G-protein-coupled receptors. Using genetically modified mice lacking A 1 and A 3 adenosine receptors, treated with ip buthionine-[ S, R]-sulphoximine injections to inhibit γ-glutamylcysteine ligase, the question was addressed whether these receptors modulate the responses to the stress related to altered glutathione levels. This study determined organ glutathione levels and expression of two sub-units of γ-glutamylcysteine ligase and the cationic x c-transporter and found that deletion of one or both adenosine receptors influenced the responses in an organ-specific manner. The lack of A 1 and A 3 adenosine receptors is related to decreased basal glutathione content and down-regulation of γ-glutamylcysteine ligase sub-units in several organs. Moreover, responses to buthionine-[ S, R]-sulphoximine were different. For example, the lack of A 3 adenosine receptors, or their blockade of A 3 by MRS 1191, caused a marked increase in gene expression, which was not observed in mice lacking both A 1 and A 3 receptors. The results indicate that A 1 and A 3 adenosine receptors play a role in antioxidant responses and their role differs in an organ-specific way. 相似文献
20.
Abstract Adenosine receptors in isolated tissues from guinea-pigs have been investigated using agonists and antagonists. The receptor mediating decreases in rate and force of contraction of the atria is of the A 1 sub-type. Responses of smooth muscle preparations to adenosine and its analogues are complex involving relaxation mediated by both A 2 receptors an by non-receptor mechanisms. Contractions mediated by an A 1 receptor can also be detected. 相似文献
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