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1.
Caffeine, a stimulant largely consumed around the world, is a non-selective adenosine receptor antagonist, and therefore caffeine actions at synapses usually, but not always, mirror those of adenosine. Importantly, different adenosine receptors with opposing regulatory actions co-exist at synapses. Through both inhibitory and excitatory high-affinity receptors (A1R and A2R, respectively), adenosine affects NMDA receptor (NMDAR) function at the hippocampus, but surprisingly, there is a lack of knowledge on the effects of caffeine upon this ionotropic glutamatergic receptor deeply involved in both positive (plasticity) and negative (excitotoxicity) synaptic actions. We thus aimed to elucidate the effects of caffeine upon NMDAR-mediated excitatory post-synaptic currents (NMDAR-EPSCs), and its implications upon neuronal Ca2+ homeostasis. We found that caffeine (30–200 μM) facilitates NMDAR-EPSCs on pyramidal CA1 neurons from Balbc/ByJ male mice, an action mimicked, as well as occluded, by 1,3-dipropyl-cyclopentylxantine (DPCPX, 50 nM), thus likely mediated by blockade of inhibitory A1Rs. This action of caffeine cannot be attributed to a pre-synaptic facilitation of transmission because caffeine even increased paired-pulse facilitation of NMDA-EPSCs, indicative of an inhibition of neurotransmitter release. Adenosine A2ARs are involved in this likely pre-synaptic action since the effect of caffeine was mimicked by the A2AR antagonist, SCH58261 (50 nM). Furthermore, caffeine increased the frequency of Ca2+ transients in neuronal cell culture, an action mimicked by the A1R antagonist, DPCPX, and prevented by NMDAR blockade with AP5 (50 μM). Altogether, these results show for the first time an influence of caffeine on NMDA receptor activity at the hippocampus, with impact in neuronal Ca2+ homeostasis. 相似文献
2.
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
3.
Hippocampal pyramidal neurons potentially express multiple subtypes of GABA A receptors at extrasynaptic locations that could therefore respond to different drugs. We activated extrasynaptic GABA A receptors in cultured rat hippocampal pyramidal neurons and measured single-channel currents in order to compare the actions
of two drugs that potentially target different GABA A receptor subtypes. Despite the possible difference in receptor targets of etomidate and diazepam, the two drugs were similar
in their actions on native extrasynaptic GABA A receptors. Each drug produced three distinct responses that differed significantly in current magnitude, implying heterogeneous
GABA A receptor populations. In the majority of patches, drug application increased both the single-channel conductance (>40 pS)
and the open probability of the channels. By contrast, in the minority of patches, drug application caused an increase in
open probability only. In the third group high-conductance channels were observed upon GABA activation and drug application
increased their open probability only. The currents potentiated by etomidate or diazepam were substantially larger in patches
displaying high-conductance GABA channels compared to those displaying only low-conductance channels. Factors contributing
to the large magnitude of these currents were the long mean open time of high-conductance channels and the presence of multiple
channels in these patches. In conclusion, we suggest that the local density of extrasynaptic GABA A receptors may influence their single-channel properties and may be an additional regulating factor for tonic inhibition and,
importantly, differential drug modulation.
This work is dedicated to the memory of Professor P. W. Gage. 相似文献
4.
GABA A receptors are the major inhibitory transmitter receptors in the central nervous system. They are chloride ion channels that can be opened by γ-aminobutyric acid (GABA) and are the targets of action of a variety of pharmacologically and clinically important drugs. GABA A receptors are composed of five subunits that can belong to different subunit classes. The existence of 19 different subunits gives rise to the formation of a large variety of distinct GABA A receptor subtypes in the brain. The majority of GABA A receptors seems to be composed of two α, two β and one γ subunit and the occurrence of a defined subunit stoichiometry and arrangement in αβγ receptors strongly indicates that assembly of GABA A receptors proceeds via defined pathways. Based on the differential ability of subunits to interact with each other, a variety of studies have been performed to identify amino acid sequences or residues important for assembly. Such residues might be involved in direct protein-protein interactions, or in stabilizing direct contact sites in other regions of the subunit. Several homo-oligomeric or hetero-oligomeric assembly intermediates could be the starting point of GABA A receptor assembly but so far no unequivocal assembly mechanism has been identified. Possible mechanisms of assembly of GABA A receptors are discussed in the light of recent publications. 相似文献
5.
Purpose: Why do anesthetics not activate excitatory ligand-gated ion channels such as 5-HT 3 receptors in contrast to inhibitory ligand-gated ion channels? This study examines the actions of structural closely-related 5-HT derivatives and 5-HT constituent parts on 5-HT 3A receptors with the aim of finding simpler if not minimal agonists and thus determining requirements for successful agonist action. Experimental approach: Responses to 5-HT derivatives of human 5-HT 3A receptors stably expressed in HEK 293 cells have been examined with the patch-clamp technique in the outside-out configuration combined with a fast solution exchange system. Results: Phenol, pyrrole and alkyl amines, constituents of 5-HT, even at high concentrations, cannot activate 5-HT 3A receptors but they can inhibit them. To date, tyramines are the smallest known agonists. However, an aromatic ring is not required for activation as acetylcholine is also an agonist of similar strength. Conclusion: Simultaneous interactions of adequate strength at two separate subsites within the 5-HT binding domain appear to be essential for successful agonist function. Anesthetics either fail to achieve this or the activation they produce is so weak that it is masked by a comparatively very strong inhibition. 相似文献
6.
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
7.
The highly potent but modestly selective N-(2-amino-4-methoxy-benzothiazol-7-yl)- N-ethyl-acetamide derivative 2 was selected as the starting point for the design of novel selective A 2B antagonists, due to its excellent potency, and good drug-like properties. A series of compounds containing nonaromatic amides or ureas of five- or six-membered rings, and also bearing an m-trifluoromethyl-phenyl group (shown to impart superior potency) was prepared and evaluated for their selectivity against the A 2A and A 1 receptors. This work resulted in the identification of compound 30, with excellent potency and high selectivity against both A 2A and A 1 receptors. 相似文献
8.
The synthesis of an important set of 3-furfurylxanthine derivatives is described. Binding affinities were determined for rat A 1 and human A 2A, A 2B and A 3 receptors. Several of the 3-furfuryl-7-methylxanthine derivatives showed moderate-to-high affinity at human A 2B receptors, the most active compound ( 10d) having a Ki of 7.4 nM for hA 2B receptors, with selectivities over rA 1 and hA 2A receptors up to 14-fold and 11-fold, respectively. Affinities for hA 3 receptors were very low for all members of the set. 相似文献
9.
Alone of the known neurotransmitters, GABA is an electroneutral zwitterion (pI=7.3) at physiological pH. This confers the highest probability of successfully traversing densely packed synaptic gaps without interacting electrostatically with charged entities enroute, making GABA a high fidelity neurotransmitter. Inhibitory tone in the nervous system is coordinately coupled with physiological activity by means of the GABA system, acidification increasing GABA formation and its Cl – channel-opening efficacy, while decreasing its removal by transport and metabolic degradation. The above, together with diminution upon acidification of the postsynaptic efficacy of glutamate on excitatory NMDA receptors constitutes a sensitively responsive mechanism by which protons control levels of neural activity, locally and globally. A model made of the GABA binding site of GABA A receptors based on H-bond and hydrophobic interactions makes it seem unlikely that any other substance known to occur in nerve tissue would give rise to a high noise level at GABA A receptors.Special issue dedicated to Dr. Claude Baxter. 相似文献
10.
Brain GABA A/benzodiazepine receptors are highly heterogeneous. This heterogeneity is largely derived from the existence of many pentameric
combinations of at least 16 different subunits that are differentially expressed in various brain regions and cell types.
This molecular heterogeneity leads to binding differences for various ligands, such as GABA agonists and antagonists, benzodiazepine
agonists, antagonists, and inverse agonists, steroids, barbiturates, ethanol, and Cl − channel blockers. Different subunit composition also leads to heterogeneity in the properties of the Cl − channel (such as conductance and open time); the allosteric interactions among subunits; and signal transduction efficacy
between ligand binding and Cl − channel opening. The study of recombinant receptors expressed in heterologous systems has been very useful for understanding
the functional roles of the different GABA A receptor subunits and the relationships between subunit composition, ligand binding, and Cl − channel properties. Nevertheless, little is known about the complete subunit composition of the native GABA A receptors expressed in various brain regions and cell types. Several laboratories, including ours, are using subunit-specific
antibodies for dissecting the heterogeneity and subunit composition of native (not reconstituted) brain GABA A receptors and for revealing the cellular and subcellular distribution of these subunits in the nervous system. These studies
are also aimed at understanding the ligand-binding, transduction mechanisms, and channel properties of the various brain GABA A receptors in relation to synaptic mechanisms and brain function. These studies could be relevant for the discovery and design
of new drugs that are selective for some GABA A receptors and that have fewer side effects. 相似文献
11.
We found that Tyr-Leu (YL) dose-dependently exhibits potent anxiolytic-like activity (0.1-1 mg/kg, i.p.) comparable to diazepam in the elevated plus-maze test in mice. YL was orally active (0.3-3 mg/kg). A retro-sequence peptide or a mixture of Tyr and Leu was inactive. The anxiolytic-like activity of YL was inhibited by antagonists for serotonin 5-HT 1A, dopamine D 1 and GABA A receptors; however, YL had no affinity for them. We also determined the order of their activation is 5-HT 1A, D 1 and GABA A receptors using selective agonists and antagonists. Taken together, YL may exhibit anxiolytic-like activity via activation of 5-HT 1A, D 1 and GABA A receptors. 相似文献
12.
Taurine appears to have multiple functions in the brain participating both in volume regulation and neurotransmission. In
the latter context it may exert its actions by serving as an agonist at receptors of the GABAergic and glycinergic neurotransmitter
systems. Its interaction with GABA A and GABA B receptors as well as with glycine receptors is reviewed and the physiological relevance of such interactions is evaluated.
The question as to whether local extracellular concentrations of taurine are likely to reach the threshold level for the pertinent
receptor populations cannot presently be answered satisfactorily. Hence more sophisticated analytical methods are warranted
in order to obtain a definite answer to this important question.
Special issue dedicated to Dr. Simo S. Oja 相似文献
13.
The discovery of new drugs for the treatment of neurodegenerative disorders, such as Parkinson's disease, has become an attractive field of research. Due to the regulation of D 2 receptor activity by A 2 A adenosine receptor, potent and selective ligands of A 2 A subtype could be useful tools to study neurodegenerative disorders. A series of 2,8-disubstituted-9-ethyladenine derivatives was synthesized and tested in binding affinity assay at human adenosine receptors. New compounds showed good affinity and selectivity at A 2 A receptor versus the other subtypes. The introduction of a bromine atom in 8-position increased the affinity of these compounds, leading to ligands with K i in the nanomolar range. 相似文献
14.
Adenosine is a neuromodulator that operates via the most abundant inhibitory adenosine A 1 receptors (A 1Rs) and the less abundant, but widespread, facilitatory A 2ARs. It is commonly assumed that A 1Rs play a key role in neuroprotection since they decrease glutamate release and hyperpolarize neurons. In fact, A 1R activation at the onset of neuronal injury attenuates brain damage, whereas its blockade exacerbates damage in adult animals. However, there is a down-regulation of central A 1Rs in chronic noxious situations. In contrast, A 2ARs are up-regulated in noxious brain conditions and their blockade confers robust brain neuroprotection in adult animals. The brain neuroprotective effect of A 2AR antagonists is maintained in chronic noxious brain conditions without observable peripheral effects, thus justifying the interest of A 2AR antagonists as novel protective agents in neurodegenerative diseases such as Parkinsons and Alzheimers disease, ischemic brain damage and epilepsy. The greater interest of A 2AR blockade compared to A 1R activation does not mean that A 1R activation is irrelevant for a neuroprotective strategy. In fact, it is proposed that coupling A 2AR antagonists with strategies aimed at bursting the levels of extracellular adenosine (by inhibiting adenosine kinase) to activate A 1Rs might constitute the more robust brain neuroprotective strategy based on the adenosine neuromodulatory system. This strategy should be useful in adult animals and especially in the elderly (where brain pathologies are prevalent) but is not valid for fetus or newborns where the impact of adenosine receptors on brain damage is different. 相似文献
15.
The structural and functional interaction between D 2 dopamine receptor (DR) and A 2A adenosine receptor (AR) has suggested these two receptors as a pharmacological target in pathologies associated with dopamine dysfunction, such as Parkinson's disease. In transfected cell lines it has been demonstrated the activation of D 2DR induces a significant negative regulation of A 2AAR-mediated responses, whereas few data are at now available about the regulation of A 2AAR by D 2DR agonists at receptor recognition site. In this work we confirmed that in A 2AAR/D 2DR co-transfected cells, these receptors exist as homo- and hetero-dimers. The classical D 2DR agonists were able to negatively modulate both A 2AAR affinity and functionality. These effects occurred even if any significant changes in A 2AAR/D 2DR energy transfer interaction could be detected in BRET experiments.Since the development of new molecules able to target A 2A/D 2 dimers may represent an attractive tool for innovative pharmacological therapy, we also identified a new small molecule, 3-(3,4-dimethylphenyl)-1-(2-piperidin-1-yl)ethyl)piperidine (compound 1), full agonist of D 2DR and modulator of A 2A-D 2 receptor dimer. This compound was able to negatively modulate A 2AAR binding properties and functional responsiveness in a manner comparable to classical D 2R agonists. In contrast to classical agonists, compound 1 led to conformational changes in the quaternary structure in D 2DR homomers and heteromers and induced A 2AAR/D 2DR co-internalization. These results suggest that compound 1 exerts a high control of the function of heteromers and could represent a starting point for the development of new drugs targeting A 2AAR/D 2 DR heteromers. 相似文献
16.
In the present study, we have investigated the effects of prolonged inhibition of nitric oxide synthase (NOS) by infusion of neuronal NOS (nNOS) inhibitor, 7-nitroindazole (7-NI), to examine modulation of NMDA and GABA A receptor binding in rat brain. The duration of sleeping time was significantly increased by the pre-treatment with 7-NI (100 mg/kg) 30 min before pentobarbital (40 mg/kg) treatment in rats. However, the duration of pentobarbital-induced sleep was shortened by the prolonged infusion of 7-NI into cerebroventricle for 7 days. We have investigated the effect of NOS inhibitor on NMDA and GABA A receptor binding characteristics in discrete areas of brain regions by using autoradiographic techniques. The GABA A receptors were analyzed by quantitative autoradiography using [ 3H]muscimol and [ 3H]flunitrazepam binding, and NMDA receptor binding was analyzed by using [ 3H]MK-801 binding in rat brain slices. Rats were infused with 7-NI (500 pmol/10 l/ h, i.c.v.) for 7 days, through pre-implanted cannula by osmotic minipumps. The levels of [ 3H]muscimol were markedly elevated in cortex, caudate putamen, and thalamus while the levels of [ 3H]flunitrazepam binding were only elevated in cerebellum by NOS inhibitor. However, there was no change in the level of [ 3H]MK-801 binding except decreasing in the thalamus. These results show that the prolonged inhibition of NOS by 7-NI-infusion highly elevates [ 3H]muscimol binding in a region-specific manner and decreases the pentobarbital-induced sleep. 相似文献
17.
Benign prostatic hypertrophy has been related with glandular ischemia processes and adenosine is a potent vasodilator agent. This study investigates the mechanisms underlying the adenosine-induced vasorelaxation in pig prostatic small arteries. Adenosine receptors expression was determined by Western blot and immunohistochemistry, and rings were mounted in myographs for isometric force recording. A 2A and A 3 receptor expression was observed in the arterial wall and A 2A-immunoreactivity was identified in the adventitia–media junction and endothelium. A 1 and A 2B receptor expression was not obtained. On noradrenaline-precontracted rings, P1 receptor agonists produced concentration-dependent relaxations with the following order of potency: 5′- N-ethylcarboxamidoadenosine (NECA) = {"type":"entrez-protein","attrs":{"text":"CGS21680","term_id":"878113053","term_text":"CGS21680"}}CGS21680 > 2-Cl-IB-MECA = 2-Cl-cyclopentyladenosine = adenosine. Adenosine reuptake inhibition potentiated both NECA and adenosine relaxations. Endothelium removal and ZM241385, an A 2A antagonist, reduced NECA relaxations that were not modified by A 1, A 2B, and A 3 receptor antagonists. Neuronal voltage-gated Ca 2+ channels and nitric oxide (NO) synthase blockade, and adenylyl cyclase activation enhanced these responses, which were reduced by protein kinase A inhibition and by blockade of the intermediate (IK Ca)- and small (SK Ca)-conductance Ca 2+-activated K + channels. Inhibition of cyclooxygenase (COX), large-conductance Ca 2+-activated-, ATP-dependent-, and voltage-gated-K + channel failed to modify these responses. These results suggest that adenosine induces endothelium-dependent relaxations in the pig prostatic arteries via A 2A purinoceptors. The adenosine vasorelaxation, which is prejunctionally modulated, is produced via NO- and COX-independent mechanisms that involve activation of IK Ca and SK Ca channels and stimulation of adenylyl cyclase. Endothelium-derived NO playing a regulatory role under conditions in which EDHF is non-functional is also suggested. Adenosine-induced vasodilatation could be useful to prevent prostatic ischemia. 相似文献
18.
Changes in lipid bilayer elastic properties have been proposed to underlie the modulation of voltage-gated Na + and L-type Ca 2+ channels and GABA A receptors by amphiphiles. The amphiphile Triton X-100 increases the elasticity of lipid bilayers at micromolar concentrations, assessed from its effects on gramicidin channel A appearance rate and lifetime in artificial lipid bilayers. In the present study, the pharmacological action of Triton-X 100 on GABA A receptors expressed in Xenopus laevis oocytes was examined. Triton-X 100 inhibited GABA A α 1β 3γ 2S receptor currents in a noncompetitive, time- and voltage-dependent manner and increased the apparent rate and extent of desensitization at 10 μM, which is 30 fold below the critical micelle concentration. In addition, Triton X-100 induced picrotoxin-sensitive GABA A receptor currents and suppressed allosteric modulation by flunitrazepam at α 1β 3γ 2S receptors. All effects were independent of the presence of a γ 2S subunit in the GABA A receptor complex. The present study suggests that Triton X-100 may stabilize open and desensitized states of the GABA A receptor through changes in lipid bilayer elasticity. 相似文献
19.
Sixteen known 5-HT 3 receptor blockers, including clozapine, fully or partially reverse the inhibitory effect of 1 M GABA on [ 35S]TBPS binding, indicating that they are also GABA A antagonists, some of them selective for subsets of GABA A receptors. The 5-HT 3 receptor blocker, ondansetron, has been reported to produce some antipsychotic and anxiolytic effects. However, no antipsychotic effects have been reported for a large number of highly potent 5-HT 3 receptor blockers. Like clozapine, ondansetron partially reverses the inhibitory effect of GABA on [ 35S]TBPS binding. Additivity experiments suggest that ten 5-HT 3 receptor blockers tested at low concentrations preferentially block subtypes of GABA A receptors that are among those blocked by clozapine. Wiley and Porter (29) reported that MDL-72222, the most potent GABA A antagonist decribed here, partially generalizes (71%) with clozapine in rats trained to discriminate an interoceptive clozapine stimulus, but only at a dose that severly decreases responding. Tropisetron (ICS-205,930) exhibits both GABA-positive and GABA-negative effects. R-(+)-zacopride is 6-fold more potent than S-(–)-zacopride as a GABA A antagonist. We conclude that the observed antipsychotic and, possibly, anxiolytic effects of some 5-HT 3 receptor blockers are due to selective antagonism of certain GABA A receptors, and not to blockade of 5-HT 3 receptors. We speculate that the anxiolytic and sedative effects of clozapine and several other antipsychotic drugs may be due to selective blockade of 122 GABA A receptors which are preferentially located on certain types of GABAergic interneurons (probably parvalbumin positive). Blockade of these receptors will increase the inhibitory output of these interneurons. So far, no highly potent GABA A antagonists with clozapine-like selectivity have been identified. Such compounds may exhibit improved clozapine-like antipsychotic activity. 相似文献
20.
The present work was undertaken to characterize kinetics, including activation, desensitization and deactivation, of responses mediated by GABA A and GABA C receptors on carp retinal bipolar cells, using the whole-cell patch-clamp technique. It was revealed that the GABA C response was generally slower in kinetics than the GABA A response. Activation kinetics of both the receptors could be well fit by monoexponential functions with time constants t, being 44.57 ms (GABA C) and 10.86 ms (GABA A) respectively. Desensitization of the GABA Aresponse was characterized by a fast and a slow exponential component with time constants of τ fast = 2.16 s and τ slow = 19.78 s respectively, whereas desensitization of the GABA C response was fit by a monoexponential function of the time constant τ = 6.98 s. Deactivation at both the receptors was adequately described by biexponential functions with time constants being much higher for the GABA C response (τ fast= 674.8 ms; τ slow = 2 090 ms) than those for the GABA A response (τ fast = 42.07 ms; τ slow = 275.1 ms). These differences in kinetics suggest that GABA C and GABA A receptors may be involved in processing signals in different frequency domains. 相似文献
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