Abstract
Adenosine is a widespread neuromodulator within the CNS and its extracellular level is increased during hypoxia or intense synaptic activity, modulating pre- and postsynaptic sites. We studied the neuromodulatory action of adenosine on glutamatergic currents in the hippocampus, showing that activation of multiple adenosine receptors (ARs) by basal adenosine impacts postsynaptic site. Specifically, the stimulation of both A1R and A3R reduces AMPA currents, while A2AR has an opposite potentiating effect. The effect of ARs stimulation on glutamatergic currents in hippocampal cultures was investigated using pharmacological and genetic approaches. A3R inhibition by MRS1523 increased GluR1-Ser845 phosphorylation and potentiated AMPA current amplitude, increasing the apparent affinity for the agonist. A similar effect was observed blocking A1R with DPCPX or by genetic deletion of either A3R or A1R. Conversely, impairment of A2AR reduced AMPA currents, and decreased agonist sensitivity. Consistently, in hippocampal slices, ARs activation by AR agonist NECA modulated glutamatergic current amplitude evoked by AMPA application or afferent fiber stimulation. Opposite effects of AR subtypes stimulation are likely associated to changes in GluR1 phosphorylation and represent a novel mechanism of physiological modulation of glutamatergic transmission by adenosine, likely acting in normal conditions in the brain, depending on the level of extracellular adenosine and the distribution of AR subtypes.
Highlights
Purinergic signaling is emerging as one important mechanism of integrating functional activity between neurons, glial and vascular cells in the brain, through the action of both ATP and adenosine signaling (Burnstock et al, 2011)
To unveil the involvement of adenosine receptors (ARs) subtypes in AMPA current modulation, cultures were treated with specific ARs antagonists, in order to establish the possible contribution of A1R, A2AR, and A3 receptors (A3R)
When control cultures were superfused with the A3R specific antagonist MRS1523 (100 nM, 8 min), we observed a significant increase in the amplitude of AMPA currents
Summary
Purinergic signaling is emerging as one important mechanism of integrating functional activity between neurons, glial and vascular cells in the brain, through the action of both ATP and adenosine signaling (Burnstock et al, 2011). Adenosine is a cellular metabolite formed by the breakdown of adenine nucleotides and is physiologically present at nanomolar to micromolar concentrations inside and outside the cells (Fredholm, 2007) It represents an endogenous modulator of brain functions, fine-tuning glial function (Boison, 2007), blood flow. It has been reported that the synaptic concentration of adenosine, tightly controlled by astrocytes and neurons, is usually higher than the intracellular one, and tonically modulates synaptic activity acting on adenosine receptors (ARs) A1R and A2AR to regulate pre or post synaptic functions (Sebastião and Ribeiro, 2014). In this study we demonstrate the ability of A3R to negatively modulate postsynaptic AMPA receptors through the reduction of GluR1 phosphorylation level This effect is synergistic with the A1R mediated reduction of AMPA currents, and counteracts the potentiating effect of A2AR activation. The concomitant activity of A1R, A2AR, and A3R tightly tunes glutamatergic synapses, setting the properties of AMPA receptors functioning in basal conditions
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