Aberrant amplification of A _2A receptor signaling in striatal cells expressing mutant huntingtin

Abstract

Huntington's disease (HD) is a neurodegenerative disorder caused by expansion of a CAG repeat in the gene encoding for Huntingtin (Htt), which results in progressive degeneration of the striatal GABAergic/enkephalin neurons. These neurons express both the A2A and D2 receptors, which stimulate and inhibit adenylyl cyclase, respectively. In this study we analyzed the possibility of an involvement of the A2A receptor and its signaling components in the pathogenesis of HD. We report here that striatal cells expressing mutant Htt exhibit increased binding affinities for the selective A2A receptor ligand 3H‐SCH‐58261. Furthermore, despite identical basal adenylyl cyclase activity in all cells, forskolin, a direct activator of this enzyme, significantly overstimulated cAMP production in mutant Htt cells with respect to parental or wild‐type Htt‐expressing cells. Michaelis‐Menten analysis of forskolin‐stimulated enzyme activity revealed a specific decrease of Km value in mutant Htt cells, indicating increased sensitivity for the substrate. Remarkably, coupling of the A2A receptor to adenylyl cyclase was also aberrantly increased. Nevertheless, in all clones, stimulation of cAMP production by 10−7 M NECA was fully counteracted by selective A2A receptor antagonists. Altogether, these data suggest that expression of mutant Htt induces an amplification of adenylyl cyclase‐transduced signals and an aberrant coupling of the A2A receptor to this transduction system. Given the involvement of adenylyl cyclase in key physiological functions, including cell growth and cell survival, we speculate that these changes may alter the susceptibility of striatal neurons to cell death and may contribute to the development of HD.

An introduction to the roles of purinergic signalling in neurodegeneration, neuroprotection and neuroregeneration

“…This selective neuronal vulnerability occurs despite ubiquitous expression of mutant and normal huntingtin suggests that these receptors might play a pathogenetic role in HD (Popoli et al, , 2008. Changes in A 2A receptor expression and signalling in both experimental models of HD (Tarditi et al, 2006) and in peripheral blood circulating cells of HD patients (Varani et al, 2001(Varani et al, , 2007) support this hypothesis. However, the functional significance of the aberrant A 2A receptor phenotype in HD is complicated by conflicting data about the potential neuroprotective and neurodegenerative effects of these receptors in the brain.…”

Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade

“…Interestingly, in clear contrast with what occurs for A 1 Rs, chronic stressful stimuli directed to the basal ganglia cause an increased expression and density of A 2A Rs, as observed in animal models of Parkinson's disease (e.g., [208,209]) and in Parkinsonian patients ( [210]; see also [211,212]). It is also possible that the expression of A 2A Rs might also increase in animal models and patients with Huntington's disease, since the expression of A 2A Rs is increased in neurons over-expressing huntingtin [213]. However, the major loss of medium spiny neurons in this condition may mask the increased density of A 2A Rs in the remaining viable neurons [211,214,215].…”

IL‐1‐regulated responses in astrocytes: Relevance to injury and recovery

“…Interestingly, recent studies have demonstrated that application of topical adenosine A2A receptor agonists promotes more rapid wound closure in skin lesions. In the CNS, blockade of 2A receptors has been shown to induce protection in various models of neurodegenerative diseases (Varani et al, 2001), and in this regard it is of interest to note that Brambilla et al (2003) have shown that exposure of primary rat striatal astrocytes to a selective A(2A) antagonist protected against induction of astrogliosis in vitro by bFGF. However, these authors also showed that the direct activation of A(2A) adenosine receptors by selective receptor agonists was not sufficient to induce a reactive astrogliosis, suggesting that the A(2A) receptor needs to act in concert with other bFGF-induced genes to trigger the formation of reactive astrocytes.…”