Aberrant amplification of A(2A) receptor signaling in striatal cells expressing mutant huntingtin.

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 H-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. MichaelisMenten 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 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.