Basal adenosine modulates the functional properties of AMPA receptors in mouse hippocampal neurons through the activation of A1R A2AR and A3R (original) (raw)
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Modulation of Hippocampal Glutamatergic Transmission by ATP Is Dependent on Adenosine A1 Receptors
Journal of Pharmacology and Experimental Therapeutics, 2002
Excitatory glutamatergic synapses in the hippocampal CA1 region of rats are potently inhibited by purines, including adenosine, ATP, and ATP analogs. Adenosine receptors are A 1 known to mediate at least part of the response to adenine nucleotides, either because adenine nucleotides activate A 1 receptors directly, or activate them secondarily upon the nucleotides' conversion to adenosine. In the present studies, the inhibitory effects of adenosine, ATP, the purportedly stable ATP analog adenosine-5′-O-(3-thio)triphosphate (ATPγS), and cyclic AMP were examined in mice with a null mutation in the adenosine A 1 receptor gene. ATPγS displaced the binding of A 1 -selective ligands to intact brain sections and brain homogenates from adenosine A 1 receptor wild-type animals. In homogenates, but not in intact brain sections, this displacement was abolished by adenosine deaminase. In hippocampal slices from wild-type mice, purines abolished synaptic responses, but slices from mice lacking functional A 1 receptors showed no synaptic modulation by adenosine, ATP, cAMP, or ATPγS. In slices from heterozygous mice the dose-response curve for both adenosine and ATP was shifted to the right. In all cases, inhibition of synaptic responses by purines could be blocked by prior treatment with the competitive adenosine A 1 receptor antagonist 8-cyclopentyltheophylline. Taken together, these results show that even supposedly stable adenine nucleotides are rapidly converted to adenosine at sites close to the A 1 receptor, and that inhibition of synaptic transmission by purine nucleotides is mediated exclusively by A 1 receptors.
Neuroscience, 2005
Adenosine is a neuromodulator that controls neurotransmitter release through inhibitory A 1 and facilitatory A 2A receptors. Although both adenosine receptor-mediated inhibition and facilitation of glutamate release have been observed, it is not clear whether both A 1 and A 2A receptors are located in the same glutamatergic nerve terminal or whether they are located on different populations of these terminals. Thus, we have tested if single pyramidal glutamatergic neurons from the hippocampus simultaneously expressed A 1 and A 2A receptor mRNA and if A 1 and A 2A receptors were co-localized in hippocampal glutamatergic nerve terminals. Single cell PCR analysis of visually identified pyramidal neurons revealed the simultaneous presence of A 1 and A 2A receptor mRNA in four out 16 pyramidal cells possessing glutamatergic markers but not GABAergic or astrocytic markers. Also, A 1 and A 2A receptor immunoreactivities were co-localized in 26؎4% of nerve terminals labeled with antibodies against vesicular glutamate transporters type 1 or 2, i.e. glutamatergic nerve terminals. This indicates that glutamatergic neurons in the hippocampus co-express A 1 and A 2A receptors and that these two receptors are co-localized in a subset of glutamatergic nerve terminals. (R. A. Cunha). Abbreviations: bp, base pairs; BSA, bovine serum albumin; GFAP, glial fibrillary acidic protein; PBS, phosphate-buffered saline; RT, reverse transcription; vGluT, vesicular glutamate transporter. Neuroscience 133 (2005) 79 -83 0306-4522/05$30.00ϩ0.00
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.
Brain Research, 1997
Electrophysiological recordings in rat brain slices have been used to study the actions of adenosine on striatal neurons and striatal excitatory amino acid neurotransmission originating in the cortex or the thalamus. Adenosine had no effects on membrane properties of striatal neurons. Adenosine and the A agonist N 6 -Cyclopentyl adenosine reduced EPSPs of both cortical and thalamic origin by more 1 than 50%. Depression of EPSPs was associated with an increase in paired-pulse facilitation, suggesting a presynaptic locus of action. X Ž . EPSP depression was blocked by the A antagonist, 8-Cyclopentyl-1,3-dipropyl xanthine. The A agonist 5 -N-cyclopropyl -carbo-1 2 xamidoadenosine had no effect on excitatory amino acid neurotransmission. The A antagonist alone enhanced the synaptic component of 1 Ž . the evoked field potential 23 " 12% . These results indicate that endogenous adenosine, acting via A receptors, limits striatal 1 glutamatergic neurotransmission, serving a modulatory and neuroprotective role. q 1997 Elsevier Science B.V.
Neuroscience, 2002
AbstractöAdenosine tonically inhibits synaptic transmission through actions at A 1 receptors. It also facilitates synaptic transmission, but it is unclear if this facilitation results from pre-and/or postsynaptic A 2A receptor activation or from indirect control of inhibitory GABAergic transmission. The A 2A receptor agonist, CGS 21680 (10 nM), facilitated synaptic transmission in the CA1 area of rat hippocampal slices (by 14%), independent of whether or not GABAergic transmission was blocked by the GABA A and GABA B receptor antagonists, picrotoxin (50 WM) and CGP 55845 (1 WM), respectively. CGS 21680 (10 nM) also inhibited paired-pulse facilitation by 12%, an e¡ect prevented by the A 2A receptor antagonist, ZM 241385 (20 nM). These e¡ects of CGS 21680 (10 nM) were occluded by adenosine deaminase (2 U/ml) and were made to reappear upon direct activation of A 1 receptors with N 6 -cyclopentyladenosine (CPA, 6 nM). CGS 21680 (10 nM) only facilitated (by 17%) the K þ -evoked release of glutamate from superfused hippocampal synaptosomes in the presence of 100 nM CPA. This e¡ect of CGS 21680 (10 nM), in contrast to the isoproterenol (30 WM) facilitation of glutamate release, was prevented by the protein kinase C inhibitors, chelerythrine (6 WM) and bisindolylmaleimide (1 WM), but not by the protein kinase A inhibitor, H-89 (1 WM). Isoproterenol (30 WM), but not CGS 21680 (10^300 nM), enhanced synaptosomal cAMP levels, indicating that the CGS 21680-induced facilitation of glutamate release involves a cAMP-independent protein kinase C activation. To discard any direct e¡ect of CGS 21680 on adenosine A 1 receptor, we also show that in autoradiography experiments CGS 21680 only displaced the adenosine A 1 receptor antagonist, 1,3dipropyl-8-cyclopentyladenosine ([ 3 H]DPCPX, 0.5 nM) with an EC 50 of 1 WM in all brain areas studied and CGS 21680 (30 nM) failed to change the ability of CPA to displace DPCPX (1 nM) binding to CHO cells stably transfected with A 1 receptors.
British Journal of Pharmacology, 1997
Glutamate and other amino acids are the main excitatory neurotransmitters in many brain regions, including the hippocampus, by activating ion channel-coupled glutamate receptors, as well as metabotropic receptors linked to G proteins and second messenger systems. Several conditions which promote the release of glutamate, like frequency stimulation and hypoxia, also lead to an increase in the extracellular levels of the important neuromodulator, adenosine. We studied whether the activation of dierent subgroups of metabotropic glutamate receptors (mGluR) could modify the known inhibitory eects of a selective adenosine A 1 receptor agonist on synaptic transmission in the hippocampus. The experiments were performed on hippocampal slices taken from young (12 ± 14 days old) rats. Stimulation was delivered to the Schaer collateral/commissural ®bres, and evoked ®eld excitatory postsynaptic potentials (fe.p.s.p.) recorded extracellularly from the stratum radiatum in the CA1 area. 2 The concentration-response curve for the inhibitory eects of the selective adenosine A 1 receptor agonist, N 6-cyclopentyladenosine (CPA; 2 ± 50 nM), on the fe.p.s.p. slope (EC 50 =12.5 (9.2 ± 17.3; 95% con®dence intervals)) was displaced to the right by the group I mGluR selective agonist, (R,S)-3,5dihydroxyphenylglycine (DPHG; 10 mM) (EC 50 =27.2 (21.4 ± 34.5) nM, n=4). The attenuation of the inhibitory eect of CPA (10 nM) on the fe.p.s.p. slope by DHPG (10 mM) was blocked in the presence of the mGluR antagonist (which blocks group I and II mGluR), (R,S)-a-methyl-4-carboxyphenylglycine (MCPG; 500 mM). DHPG (10 mM) itself had an inhibitory eect of 20.1+1.9% (n=4) on the fe.p.s.p. slope. 3 The concentration-response curves for the inhibitory eects of CPA (2 ± 20 nM) on the fe.p.s.p. slope were not modi®ed either in the presence of the group II mGluR selective agonist, (2S,3S,4S)-a-(carboxycyclopropyl)glycine (L-CCG-I; 1 mM), or in the presence of the non-selective mGluR agonist (which activates both group I and II mGluR), (1S,3R)-1-aminocyclopentyl-1,3-dicarboxylate (ACPD; 100 mM). L-CCG-I had no consistent eects and ACPD (100 mM) decreased by 19.4+1.8% (n=4) the fe.p.s.p. slope. 4 The concentration-response curve for the inhibitory eects of CPA (2 ± 100 nM) on the fe.p.s.p. slope (EC 50 =8.2 (6.9 ± 9.6) nM) was displaced to the right by the group III mGluR selective agonist, L-2amino-4-phosphonobutyrate (L-AP4; 25 mM) (EC 50 =17.7 (13.1 ± 21.9) nM, n=4). The attenuation of the inhibitory eect of CPA (10 nM) on the fe.p.s.p. slope by L-AP4 (25 mM) was blocked in the presence of the mGluR antagonist (selective for the group III mGluR), (R,S)-a-methyl-4-phosphonophenylglycine (MPPG; 200 mM). 5 Both the direct eect of DHPG on synaptic transmission and the attenuation of the inhibitory eect of CPA (10 nM) were prevented in the presence of the protein kinase C selective inhibitors, staurosporine (1 mM) or chelerythrine (5 mM), and thus attributed to activation of protein kinase C. 6 The attenuation by L-AP4 (25 mM) of the inhibitory eect of CPA (10 nM) on the fe.p.s.p. slope was also prevented by the protein kinase C selective inhibitors, staurosporine (1 mM) or chelerythrine (5 mM), and thus attributed to activation of protein kinase C. But this eect seemed to be distinct from the direct eect of L-AP4 (25 mM) on synaptic transmission, which was not modi®ed by the protein kinase C selective inhibitors. 7 We conclude that agonists of metabotropic glutamate receptors (Groups I and III) are able to attenuate the inhibitory eects of adenosine A 1 receptor activation in the hippocampus. This interaction may have pathophysiological relevance in hypoxia, in which there is marked release of both excitatory amino acids and the important endogenous neuroprotective substance, adenosine.
The Journal of …, 2006
This provides a switch mechanism by which low and high concentrations of adenosine inhibit and stimulate, respectively, glutamate release. Furthermore, it is also shown that A 1 R-A 2A R heteromers constitute a unique target for caffeine and that chronic caffeine treatment leads to modifications in the function of the A 1 R-A 2A R heteromer that could underlie the strong tolerance to the psychomotor effects of caffeine.
Adenosine A1 receptors presynaptically modulate excitatory synaptic input onto subiculum neurons
Brain Research, 2009
Adenosine is an endogenous neuromodulator previously shown to suppress synaptic transmission and membrane excitability in the CNS. In this study we have determined the actions of adenosine on excitatory synaptic transmission in the subiculum, the main output area for the hippocampus. Adenosine (10 μM) reversibly inhibited excitatory post synaptic currents (EPSCs) recorded from subiculum neurons. These actions were mimicked by the A 1 receptor specific agonist, N 6cyclopentyl-adenosine (CPA, 10 nM) and blocked by the A 1 receptor antagonist 8-cyclopentyl-1,3dipropylxanthine (DPCPX, 500 nM), but were unaffected by the A 2A antagonist ZM 241385 (50 nM). In membrane excitability experiments, bath application of adenosine and CPA reversibly inhibited action potentials (AP) in subiculum neurons that were evoked by stimulation of the pyramidal cell layer of the CA1, but not by depolarizing current injection steps in subiculum neurons, suggesting a presynaptic mechanism of action. In support, adenosine and CPA application reduced mEPSC frequency without modulating mEPSC amplitude. These studies suggest that modulation of subiculum neuron excitability by adenosine is mediated via presynaptic A 1 receptors.
Evidence for functionally important adenosine A2a receptors in the rat hippocampus
Brain Research, 1994
Adenosine A2a receptors are not confined to dopamine-rich areas of the brain, since thermocycling analysis shows that adenosine A2a receptor mRNA is expressed also in the hippocampus (CA1, CA3 and dentate gyrus) and cerebral cortex. The expression of Aza mRNA in three main areas of the hippocampus was confirmed by in situ hybridization; A2~ mRNA expression was mainly localized in the pyramidal and granular cells, the same hippocampal regions that showed adenosine A I receptor mRNA expression. Receptor autoradiographic studies with [3H]CGS 21680 (30 nM), a selective adenosine Az~ receptor agonist, showed specific binding sites in the hippocampus. The density of [3H]CGS 21680 binding was greatest in the stratum radiatum of the CA1 area, followed by the stratum oriens of the cornu Ammonis, stratum radiatum of the CA3 area and supra-granular layer of the dentate gyrus. This anatomical distribution of [3H]CGS 21680 binding was similar to the pattern of [3H]CHA binding in the hippocampus. Electrophysiological studies in the Schaffer fibers/CA1 pyramids showed that upon activation of the A2~ , receptors with CGS 21680 (10 nM) the ability of the adenosine A~ receptor agonist, CPA, to inhibit neuronal activity was significantly attenuated. These results show functionally important co-expression and co-localization of adenosine A2~, and A l receptors in the hippocampus. The results also suggest that adenosine A2a receptor-mediated neuromodulation is not confined to the basal ganglia, but is more widespread throughout the nervous system.