Purinergic modulation of norepinephrine release and uptake in rat brain cortex: contribution of glial cells

Abstract

Pinho D, Quintas C, Sardo F, Cardoso TM, Queiroz G. Purinergic modulation of norepinephrine release and uptake in rat brain cortex: contribution of glial cells. J Neurophysiol 110: 2580 -2591, 2013. First published September 11, 2013 doi:10.1152/jn.00708.2012.-The pathogenesis of psychiatric and neurodegenerative diseases is often associated with a deregulation of noradrenergic transmission. Considering the potential involvement of purinergic signaling in the modulation of noradrenergic transmission in the brain cortex, this study aimed to identify the P2Y receptor subtypes involved in the modulation of neuronal release and neuronal/glial uptake of norepinephrine. Electrical stimulation (100 pulses at 5 Hz) of rat cortical slices induced norepinephrine release that was inhibited by ATP and ADP (0.01-1 mM), adenosine 5=-O-(2-thiodiphosphate) (ADP␤S, 0.03-0.3 mM), and UDP (0.1-1 mM). The effect of ADP␤S was mediated by P2Y 1 receptors and possibly by A 1 /P2Y 1 heterodimers since it was attenuated by the A 1 receptor antagonist DPCPX and by the P2Y 1 receptor antagonist MRS 2500 but was resistant to the effect of adenosine deaminase (ADA). UDP inhibited norepinephrine release through activation of P2Y 6 receptors, an effect that was abolished by the P2Y 6 receptor antagonist MRS 2578 and by DPCPX, indicating that it depends on the formation and/or release of adenosine and activation of A 1 receptors. Supporting this hypothesis, the inhibitory effect of UDP was also prevented by inhibition of ectonucleotidases, by ADA and was attenuated by the inhibitor of nucleoside transporter 6-[(4-nitrobenzyl)thio]-9-␤-D-ribofuranosylpurine (NBTI). Additionally, the inhibitory effect of UDP was attenuated when norepinephrine uptake 1 or 2 was inhibited. In astroglial cultures, ADP␤S and UDP increased norepinephrine uptake mainly by activation of P2Y 1 and P2Y 6 receptors, respectively. The results indicate that neuronal and glial P2Y 1 and P2Y 6 receptors may represent new targets of intervention to regulate noradrenergic transmission in CNS diseases. adenosine receptors; P2Y receptors; glial norepinephrine uptake; glia-neuron communication

Overexpression of GRK6 alleviates chronic visceral hypersensitivity through downregulation of P2Y6 receptors in anterior cingulate cortex of rats with prenatal maternal stress

“…It is reported that P2Y6 was mainly expressed in microglia and astrocytes 31–33 . To confirm the distribution of P2Y6 in ACC, different cell markers were used for immunofluorescence study.…”

“…It is reported that P2Y6 was mainly expressed in microglia and astrocytes. [31][32][33] To confirm the distribution of P2Y6 in ACC, different cell markers were used for immunofluorescence study. Surprisingly, P2Y6 was predominately co-localized with NeuN, but only a few with Iba1 and GFAP (Figure 5A).…”

Inosine Strongly Enhances Proliferation of Human C32 Melanoma Cells through PLC‐PKC‐MEK1/2‐ERK1/2 and PI3K Pathways

“…Cells were allowed to attach for 24 hr and then were treated with ADA (0.3 U/mL ) or increasing concentrations of nucleosides (ADO or INO) for different time points (1–48 hr), depending on the experiment performed. When antagonists (MRE 3008F20 (selective A 3 AR, 10 nM ); CGS 15943 (non‐selective AR, 100 nM ); MRS 2500 (selective P2Y 1 R, 1 μM )) were used, these compounds were added 30 min. prior to the addition of other compounds.…”

Pharmacological Tools to Activate Microglia and their Possible use to Study Neural Network Patho-physiology

“…P2Y6 is expressed in microglia, but not in astrocytes [ 152 , 153 ], although there is a pharmacological report suggesting the presence of P2Y6 in cultured astrocytes [ 154 , 155 ], and some reports locate P2Y6 in subsets of neurons, mainly in the periphery [ 156 , 157 ]. Interestingly, the expression P2Y6 in microglia is sensitive to neuronal excitability [ 158 ].…”