A1R–A2AR heteromers coupled to Gs and Gi/0 proteins modulate GABA transport into astrocytes

Cristóvão-Ferreira, Sofia; Navarro, Gemma; Brugarolas, Marc; Pérez-Capote, Kamil; Vaz, Sandra H.; Fattorini, Giorgia; Conti, Fiorenzo; Lluı́s, Carmen; Ribeiro, Joaquim A.; McCormick, Peter J.; Casadó, Vicent; Franco, Rafael; Sebastião, Ana M.

doi:10.1007/s11302-013-9364-5

Cited by 123 publications

(121 citation statements)

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“…On the other hand, adenosine A 2A receptor-mediated GABA uptake by neighboring astrocytes may contribute to neuronal excitation [14], since astroglia dominate the buildup of extrasynaptic GABA that controls the glutamatergic neuronal excitatory drive. In a previous study, Cristovão-Ferreira et al [30] elegantly demonstrated that higher extracellular adenosine levels, such as those occurring during epileptic crisis, favor astrocytic GABA uptake by switching the coupling of A 1 /A 2A heteromers from inhibitory G i to excitatory G s protein proteins signaling. Mixed signal transduction and lateral stabilization of A 1 /A 2A heteromers in the 2:2 conformation has been confirmed recently in heterologous systems [56], but the pathophysiological consequences of altered receptors stoichiometry motivated by epileptic changes is worth to be investigated in the near future.…”

Section: Resultsmentioning

confidence: 99%

“…Astrocytes modulate the activity of neuronal networks upon sustained and intense activity, but it has been recently evidenced that astrocytes can also modulate basal synaptic transmission by the release of purines [29]. Interestingly, γ-aminobutyric acid (GABA) uptake in astrocytes has been attributed to the expression of A 1 /A 2A heteromers and to a specific mechanism by which these heteromers signal via inhibitory G i or facilitatory G s depending on the extracellular concentration of adenosine [30]. The astrocytic A 2A receptor also seems to be critical for the modulation of glutamate transport, either by decreasing the uptake [12,13] or increasing the release [11] of this amino acid.…”

Section: Introductionmentioning

confidence: 99%

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Adenosine A2A receptor and ecto-5′-nucleotidase/CD73 are upregulated in hippocampal astrocytes of human patients with mesial temporal lobe epilepsy (MTLE)

Barros‐Barbosa

Ferreirinha

Oliveira

et al. 2016

Purinergic Signalling

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Refractoriness to existing medications of up to 80 % of the patients with mesial temporal lobe epilepsy (MTLE) prompts for finding new antiepileptic drug targets. The adenosine A 2A receptor emerges as an interesting pharmacological target since its excitatory nature partially counteracts the dominant antiepileptic role of endogenous adenosine acting via inhibitory A 1 receptors. Gain of function of the excitatory A 2A receptor has been implicated in a significant number of brain pathologies commonly characterized by neuronal excitotoxicity. Here, we investigated changes in the expression and cellular localization of the A 2A receptor and of the adenosine-generating enzyme, ecto-5′-nucleotidase/ CD73, in the hippocampus of control individuals and MTLE human patients. Western blot analysis indicates that the A 2A receptor is more abundant in the hippocampus of MTLE patients compared to control individuals. Immunoreactivity against the A 2A receptor predominates in astrocytes staining positively for the glial fibrillary acidic protein (GFAP). No colocalization was observed between the A 2A receptor and neuronal cell markers, like synaptotagmin 1/2 (nerve terminals) and neurofilament 200 (axon fibers). Hippocampal astrogliosis observed in MTLE patients was accompanied by a proportionate increase in A 2A receptor and ecto-5′-nucleotidase/CD73 immunoreactivities. Given our data, we hypothesize that selective blockade of excessive activation of astrocytic A 2A receptors and/or inhibition of surplus adenosine formation by membrane-bound ecto-5′-nucleotidase/CD73 may reduce neuronal excitability, thus providing a novel therapeutic target for drug-refractory seizures in MTLE patients. • Ecto-5′-nucleotidase/CD73 localizes in close proximity with adenosine A 2A receptors in astrocytes of the human hippocampus. Keywords Mesial temporal lobe epilepsy (MTLE• Up-regulation of A 2A receptors and ecto-5′-nucleotidase/CD73 associates with astrogliosis of the hippocampus of MTLE patients.• Targeting astrocytic A 2A activation and/or adenosine formation via ecto-5′-nucleotidase/CD73 may control neuronal excitability.• Inhibitors of astrocytic A 2A receptors and ecto-5′-nucleotidase/CD73 may be a novel therapeutic strategy to control drug-refractory MTLE.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Adenosine A2A receptor and ecto-5′-nucleotidase/CD73 are upregulated in hippocampal astrocytes of human patients with mesial temporal lobe epilepsy (MTLE)

Barros‐Barbosa

Ferreirinha

Oliveira

et al. 2016

Purinergic Signalling

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“…In addition, BDNF facilitates exocytotic GABA release (B) (present work) and astrocytic GAT-1-mediated uptake of GABA (C) [17]; in both cases, these actions are gated by A 2A R. Direct influences of adenosine over hippocampal GABAergic transmission also occur, and some involving A 2A Rs are depicted in this figure (see [2] for details). Thus, A 2A Rs also directly facilitate GAT-1-mediated GABA transport into nerve endings (A) [52] as well as facilitate GAT-1-and GAT-3-mediated GABA transport into astrocytes (C), these actions being counteracted by an inhibitory action mediated by A 1 R which is heteromerized with A 2A R at the plasma membrane of the astrocytes (C) [53]. Altogether, these A 2A R-dependent actions of BDNF may contribute to increase neuronal excitability without losing temporal fidelity of GABA transmission of GABAergic signaling but also be shortening the time window of GABA action, so increasing, in this way, the temporal fidelity of GABAergic transmission.…”

Section: Discussionmentioning

confidence: 99%

BDNF-induced presynaptic facilitation of GABAergic transmission in the hippocampus of young adults is dependent of TrkB and adenosine A2A receptors

Colino-Oliveira

Rombo

Dias

et al. 2016

Purinergic Signalling

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Brain-derived neurotrophic factor (BDNF) and adenosine are widely recognized as neuromodulators of glutamatergic transmission in the adult brain. Most BDNF actions upon excitatory plasticity phenomena are under control of adenosine A 2A receptors (A 2A Rs). Concerning gammaaminobutyric acid (GABA)-mediated transmission, the available information refers to the control of GABA transporters. We now focused on the influence of BDNF and the interplay with adenosine on phasic GABAergic transmission. To assess this, we evaluated evoked and spontaneous synaptic currents recorded from CA1 pyramidal cells in acute hippocampal slices from adult rat brains (6 to 10 weeks old). BDNF (10-100 ng/mL) increased miniature inhibitory postsynaptic current (mIPSC) frequency, but not amplitude, as well as increased the amplitude of inhibitory postsynaptic currents (IPSCs) evoked by afferent stimulation. The facilitatory action of BDNF upon GABAergic transmission was lost in the presence of a Trk inhibitor (K252a, 200 nM), but not upon p75 NTR blockade (anti-p75 NTR IgG, 50 μg/mL). Moreover, the facilitatory action of BDNF onto GABAergic transmission was also prevented upon A 2A R antagonism (SCH 58261, 50 nM). We conclude that BDNF facilitates GABAergic signaling at the adult hippocampus via a presynaptic mechanism that depends on TrkB and adenosine A 2A R activation.

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“…[130][131][132][133][134] This same interaction is also seen in cultured cortical astrocytes, where activation of the A 1 R-A 2A R heteromer has a modulatory effect on GABA uptake. 135 In dopaminergic terminals, only A 1 R are expressed, resulting in the tonic inhibition of dopamine release. 132 Postsynaptically, A 1 R and A 2A R are highly expressed in the somatodendritic region of striatal MSNs, and particularly, in the dendritic spines.…”

Section: Striatal Adenosine Neurotransmissionmentioning

confidence: 99%

The Role of Adenosine Tone and Adenosine Receptors in Huntington's Disease

Blum

Chern

Domenici

et al. 2018

Journal of Caffeine and Adenosine Research

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Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by a mutation in the IT15 gene that encodes for the huntingtin protein. Mutated hungtingtin, although widely expressed in the brain, predominantly affects striato-pallidal neurons, particularly enriched with adenosine A 2A receptors (A 2A R), suggesting a possible involvement of adenosine and A 2A R is the pathogenesis of HD. In fact, polymorphic variation in the ADORA2A gene influences the age at onset in HD, and A 2A R dynamics is altered by mutated huntingtin. Basal levels of adenosine and adenosine receptors are involved in many processes critical for neuronal function and homeostasis, including modulation of synaptic activity and excitotoxicity, the control of neurotrophin levels and functions, and the regulation of protein degradation mechanisms. In the present review, we critically analyze the current literature involving the effect of altered adenosine tone and adenosine receptors in HD and discuss why therapeutics that modulate the adenosine system may represent a novel approach for the treatment of HD.Keywords: Huntington's disease, adenosine, adenosine receptors, equilibrative nucleoside transporter, animal models Pathogenic Mechanisms of Huntington's DiseaseOverview H untington's disease (HD) is an inherited neurodegenerative disorder that is caused by a single, autosomal dominant gene mutation. HD generally affects young adults and is characterized by involuntary, abnormal movements and postures (chorea, dyskinesia, dystonia), psychiatric disturbances, and cognitive alterations.1,2 It is estimated that 1 in 10,000 people have HD and this disorder is fatal within 15-20 years after the onset of symptoms. Multiple brain regions, including several cortical and subcortical regions (cerebral cortex, layers III, V, and VI; pallidum, sub-thalamic nucleus, cerebellum), show signs of neurodegeneration, but the most pronounced neuronal loss is present in the caudate nucleus and the putamen of the striatum.3 Within the striatum, the striato-pallidal, medium spiny neurons (MSN) that express enkephalin, dopamine D 2 receptors (D 2 R) and adenosine A 2A receptors (A 2A R), 4,5 appear to be the most vulnerable.6,7

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A1R–A2AR heteromers coupled to Gs and Gi/0 proteins modulate GABA transport into astrocytes

Cited by 123 publications

References 40 publications

Adenosine A2A receptor and ecto-5′-nucleotidase/CD73 are upregulated in hippocampal astrocytes of human patients with mesial temporal lobe epilepsy (MTLE)

Adenosine A2A receptor and ecto-5′-nucleotidase/CD73 are upregulated in hippocampal astrocytes of human patients with mesial temporal lobe epilepsy (MTLE)

BDNF-induced presynaptic facilitation of GABAergic transmission in the hippocampus of young adults is dependent of TrkB and adenosine A2A receptors

The Role of Adenosine Tone and Adenosine Receptors in Huntington's Disease

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