Publicação

Setting GABA levels : GABA transporters modulation by adenosine receptors

Detalhes bibliográficos
Resumo:	Gamma-aminobutyric acid is the main inhibitory neurotransmitter in central nervous system. To assure a controlled GABAergic transmission GABA must be quickly removed from synapse, which occurs through specific transporters expressed both in pre-synaptic terminal (GAT-1) and surrounding astrocytes (GAT-1 and GAT-3). Adenosine, which is a well-known neuromodulator, promotes GABA release in the hippocampus (Cunha and Ribeiro, 2000). The main goal of this thesis was to identify a possible role of adenosine upon GABA uptake into pre-synaptic terminals and into astrocytes. In pre-synaptic terminals, the removal of endogenous adenosine by ADA inhibited GABA uptake, an effect that was mimicked by the blockade of A2A receptors. Thus, endogenous adenosine, through the activation of A2A receptors, promotes GABA uptake into pre-synaptic terminals. Experiments with activators and inhibitors of transduction pathways revealed that AC/cAMP/PKA is the transduction pathway associated with this effect. In fact, the activation of PKA restrains an inhibitory tonic influence mediated by PKC, resulting in an increase of GABA uptake. The increase of transport rate occurs through the enhancement of the expression of GAT-1 at the surface membrane. In astrocytes, adenosine has a biphasic effect upon GABA uptake. This biphasic effect is mediated by the adenosine A1-A2A receptors heteromers, whose presence in astrocytes was identified in this work. The adenosine A1-A2A receptor heteromer is coupled to both Gi/0 and Gs protein, being AC/cAMP/PKA the intracellular pathway associated. At low concentration, adenosine activates the A1 protomer, which through Gi/0 protein inhibit AC, decreasing PKA activity and consequently, GABA uptake mediated by both GAT-1 and GAT-3. When adenosine levels rise, adenosine activates preferentially the A2A protomer, which through Gs activity enhances PKA activity, promoting GABA uptake into astrocytes. The adenosine A1-A2A receptors heteromer can be viewed as a unique entity since it reaches and leaves the membrane as an entire complex and all the components have to be available for the heteromer be functional. Moreover, this work clearly showed that the heteromer is associated with both Gs and Gi/0, being a tetramer of A1-A1-A2A-A2A, rather than an A1-A2A complex coupled to Gq as previously thought. Globally, at tripartite synapse level, adenosine controls the final destination of GABA after its release into the synapse. At low levels, adenosine will inhibit uptake into astrocytes but promote the uptake of GABA into presynaptic terminals, therefore facilitating the inhibitory phasic and tonic transmission. At higher levels of adenosine, GABA uptake into astrocytes will be favoured, which may decrease GABAergic tonic transmission, therefore facilitating excitability. In conclusion, this work highlighted a yet unknown mechanism through which adenosine may contribute to the switch between inhibition and excitation, through a concerted cross-talk between astrocytes and inhibitory neurons.
Autores principais:	Ferreira, Ana
Assunto:	Ácido gama-aminobutírico (GABA) Adenosina desaminase Difosfato de adenosina Adenosina quinase Teses de doutoramento - 2012
Ano:	2012
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