Adenosine and glutamate extracellular concentrations and mitogen-activated protein kinases in the striatum of Huntington transgenic mice. Selective antagonism of adenosine A2A receptors reduces transmitter outflow

A Critical Evaluation of Adenosine A2A Receptors as Potentially “Druggable” Targets in Huntingtons Disease

“…This finding is in line with the idea that A 2A R ligands can exert very different effects in systems expressing mutant vs WT huntingtin [78,93]. In agreement, in microdialysis experiments, SCH 58261 was reported to reduce basal glutamate outflow in R6/2 but not in WT mice [178] and, while in corticostriatal slices from WT mice the activation of A 2A Rs increased NMDA-induced toxicity, in frankly symptomatic R6/2 mice it decreases it [91]. Altogether these findings suggest a change in the A 2A R functionality in HD.…”

Modulation of Ca2+-currents by sequential and simultaneous activation of adenosine A1 and A2A receptors in striatal projection neurons

“…Basal extracellular levels are ca. 40-120 nM [50][51][52][53][54][55], while micromolar concentrations are reached during more intense neuronal discharge [52,[56][57][58]. Low [basal] adenosine concentrations stimulate A 1 -receptors [46,59,60], while high concentrations activate A 2A -receptors [37,45,46,[60][61][62].…”

Local Glutamate Level Dictates Adenosine A2AReceptor Regulation of Neuroinflammation and Traumatic Brain Injury

“…The cAMP-PKA pathway has been identified as the main signaling cascade responsible for A 2A R-mediated inhibition of acute inflammation (Cronstein, 1994;Haskó and Cronstein, 2004;Sitkovsky et al, 2004;Fredholm et al, 2007). However, A 2A R activation can signal through cAMP-PKA independent pathways as well (Fredholm et al, 2007), including PKC (Lai et al, 1997;Cunha and Ribeiro, 2000;Pinto-Duarte et al, 2005), MAPK (mitogen-activated protein kinase) (Cheng et al, 2002;Schulte and Fredholm, 2003;Gianfriddo et al, 2004;Melani et al, 2006), ␤-arrestin (Khoa et al, 2006), and even Src-TrkA pathway (Malek et al, 1999). In addition, recent studies show that the C terminus of the A 2A R binds to several interacting proteins [actinin, ARNO (ARF nucleotide binding site opener), Usp4, and TRAX (Translin-associated factor X)] and might mediate the G-protein-independent function of A 2A Rs (for review, see Fredholm et al, 2007).…”