Publicação
Modulation of glutamat AMPA receptors by adenosine, in physiological and hypoxic/ischemic conditions
| Resumo: | Most of the fast excitatory transmission in the brain is conveyed by ionotropic glutamate a-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA) receptors, formed by tetrameric assemblies of different subunit (GluR1-GluR4) composition. Modulation of AMPA receptors enables profound changes in synaptic efficiency, underlying the maturation of neuronal networks throughout development and plasticity, but also glutamate-mediated excitotoxicity. Accurate tuning of AMPA function can be attained by subunit phosphorylation, affecting channel properties and receptor trafficking rates. Accordingly, activation of noradrenergic and dopaminergic metabotropic receptors positively modulates AMPA receptor function through increased PKA activity and GluR1 phosphorylation, an effect restricted to brain areas targeted by pathways relying on these neurotransmitters. In contrast, adenosine is ubiquitously present throughout the nervous system, being released by glia and neurons or derived from the extracellular catabolism of adenine nucleotides. The present work thus aimed at evaluating the modulation of postsynaptic AMPA receptors by high-affinity, G-coupled A1 and A2A adenosine receptors and its implications for long term potentiation (LTP), widely perceived as the cellular correlate for memory formation (chapter 5.1). The involvement of A2A (chapter 5.2) and A1 (chapter 5.3) receptormediated tuning of glutamatergic transmission was further addressed in excitotoxicity conditions. Exogenous activation of A2A receptors by 2- [4-(2-p-carboxyethyl)phenylamino]-50-N-ethylcarboxamidoadenosine (CGS21680) was found to significantly facilitate AMPA-evoked currents in CA1 pyramidal neurons, by a postsynaptic PKA-dependent mechanism leading to increased GluR1 membrane expression. The functional impact of this modulation was evidenced by LTP facilitation at the CA3-CA1 synapse, following brief CGS21680 application. Moreover, endogenous A2A receptor activation was required for ischemia-induced facilitation of glutamatergic transmission, revealing a conserved regulatory mechanism between both forms of plasticity, which may be of interest for functional recovery (through circuit rewiring) from stroke. Additionally, results suggests that some (OSM), but not all (LIF) immunoregulatory cytokines of the IL-6 family can exert neuroprotection from hypoxia through upregulation of A1 receptors, to tone down synaptic transmission and consequently, energy expenditure. |
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| Autores principais: | Dias, Raquel Alice da Silva Baptista, 1983- |
| Assunto: | Receptores de AMPA Adenosina Anóxia Hipóxia-isquemia encefálica Isquémia Neurociências Teses de doutoramento - 2011 |
| Ano: | 2011 |
| País: | Portugal |
| Tipo de documento: | tese de doutoramento |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | Most of the fast excitatory transmission in the brain is conveyed by ionotropic glutamate a-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA) receptors, formed by tetrameric assemblies of different subunit (GluR1-GluR4) composition. Modulation of AMPA receptors enables profound changes in synaptic efficiency, underlying the maturation of neuronal networks throughout development and plasticity, but also glutamate-mediated excitotoxicity. Accurate tuning of AMPA function can be attained by subunit phosphorylation, affecting channel properties and receptor trafficking rates. Accordingly, activation of noradrenergic and dopaminergic metabotropic receptors positively modulates AMPA receptor function through increased PKA activity and GluR1 phosphorylation, an effect restricted to brain areas targeted by pathways relying on these neurotransmitters. In contrast, adenosine is ubiquitously present throughout the nervous system, being released by glia and neurons or derived from the extracellular catabolism of adenine nucleotides. The present work thus aimed at evaluating the modulation of postsynaptic AMPA receptors by high-affinity, G-coupled A1 and A2A adenosine receptors and its implications for long term potentiation (LTP), widely perceived as the cellular correlate for memory formation (chapter 5.1). The involvement of A2A (chapter 5.2) and A1 (chapter 5.3) receptormediated tuning of glutamatergic transmission was further addressed in excitotoxicity conditions. Exogenous activation of A2A receptors by 2- [4-(2-p-carboxyethyl)phenylamino]-50-N-ethylcarboxamidoadenosine (CGS21680) was found to significantly facilitate AMPA-evoked currents in CA1 pyramidal neurons, by a postsynaptic PKA-dependent mechanism leading to increased GluR1 membrane expression. The functional impact of this modulation was evidenced by LTP facilitation at the CA3-CA1 synapse, following brief CGS21680 application. Moreover, endogenous A2A receptor activation was required for ischemia-induced facilitation of glutamatergic transmission, revealing a conserved regulatory mechanism between both forms of plasticity, which may be of interest for functional recovery (through circuit rewiring) from stroke. Additionally, results suggests that some (OSM), but not all (LIF) immunoregulatory cytokines of the IL-6 family can exert neuroprotection from hypoxia through upregulation of A1 receptors, to tone down synaptic transmission and consequently, energy expenditure. |
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