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Adenosine A2A receptors enhance GABA transport into nerve terminals by restraining PKC inhibition of GAT-1
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Orientador(es)
Resumo(s)
Neurotransmitter transporters are regulated by phosphorylation but little is known about endogenous substances and receptors that regulate this process. Adenosine is an ubiquitous neuromodulator operating G-protein coupled receptors, which affect the activity of several kinases. We therefore evaluated the influence of adenosine upon the GABA transporter 1 (GAT-1) mediated GABA uptake into hippocampal synaptosomes.
Removal of endogenous adenosine (adenosine
deaminase, 1 U/mL) decreased GABA uptake, an effect mimicked by blockade of A2A receptors (2-(2-furanyl)-7-(2-phenylethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine, 50 nM) but not A1 or A2B receptors. A2A receptor activation (4-[2-[[6-amino-9-(N-ethyl-b-D-ribofuranuronamidosyl)- 9H-purin-yl]amino]ethyl]benzenepropanoic acid hydrochloride, 3–100 nM) enhanced GABA uptake by increasing the transporter Vmax without change of KM. This was mimicked by
adenylate cyclase activation (forskolin, 10 lM) and prevented by protein kinase A (PKA) inhibition (N-[2-(p-bromocinnamylamino)
ethyl]-5-isoquinolinesulfonamide dihydrochloride, 1 lM), which per se did not influenceGABAtransport. Blockade of protein kinase C (PKC) (2-[1-(3-dimethylaminopropyl)indol- 3-yl]-3-(indol-3-yl) maleimide, 1 lM) facilitated GABA transport whereas PKC activation (4-b-phorbol-didecanoate, 250 nM)
inhibited it. PKA blockade did not affect the facilitatory action of the PKC inhibitor or the inhibitory action of the PKC activator.
However, when adenylate cyclase was activated neither activation
nor inhibition of PKC affected GABA uptake. It is concluded that A2A receptors, through activation of the adenylate cyclase/cAMP/PKA transducing pathway facilitate GAT-1
mediated GABA transport into nerve endings by restraining tonic PKC-mediated inhibition.
Descrição
© 2009 International Society for Neurochemistry © 2009 The Authors
The definitive version is available at www3.interscience.wiley.com][A versão definitiva está disponível em www3.interscience.wiley.com]
The definitive version is available at www3.interscience.wiley.com][A versão definitiva está disponível em www3.interscience.wiley.com]
Palavras-chave
A2A receptors Adenosine GABA transport GABA transporter 1 Protein kinase A Protein kinase C
Contexto Educativo
Citação
Journal of Neurochemistry | 2009 | 109 | 336–347