A novel Gαs-binding protein, Gas-2 like 2, facilitates the signaling of the A2A adenosine receptor.

The A2A adenosine receptor (A2AR) is a G-protein-coupled receptor that contains a long cytoplasmic carboxyl terminus (A2AR-C). We report here that Gas-2 like 2 (G2L2) is a new interacting partner of A2AR-C. The interaction between A2AR and G2L2 was verified by GST pull-down, co-immunoprecipitation, immunocytochemical staining, and fluorescence resonance energy transfer. Expression of G2L2 increased the intracellular cAMP content evoked by A2AR in an A2AR-C-dependent manner. Immunoprecipitation and pull-down assays demonstrated that G2L2 selectively bound to A2AR-C and the inactive form of Gαs to facilitate the recruitment of the trimeric G protein complex to the proximal position of A2AR for efficient activation. Collectively, G2L2 is a new effector that controls the action of A2AR by modulating its ability to regulate the Gαs-mediated cAMP contents.

CGS21680 attenuates symptoms of Huntington's disease in a transgenic mouse model.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a CAG trinucleotide expansion in exon 1 of the Huntingtin (Htt) gene. We show herein that in an HD transgenic mouse model (R6/2), daily administration of CGS21680 (CGS), an A(2A) adenosine receptor (A(2A)-R)-selective agonist, delayed the progressive deterioration of motor performance and prevented a reduction in brain weight. 3D-microMRI analysis revealed that CGS reversed the enlarged ventricle-to-brain ratio of R6/2 mice, with particular improvements in the left and right ventricles. (1)H-MRS showed that CGS significantly reduced the increased choline levels in the striatum. Immunohistochemical analyses further demonstrated that CGS reduced the size of ubiquitin-positive neuronal intranuclear inclusions (NIIs) in the striatum of R6/2 mice and ameliorated mutant Htt aggregation in a striatal progenitor cell line overexpressing mutant Htt with expanded polyQ. Moreover, chronic CGS treatment normalized the elevated blood glucose levels and reduced the overactivation of a major metabolic sensor [5'AMP-activated protein kinase (AMPK)] in the striatum of R6/2 mice. Since AMPK is a master switch for energy metabolism, modulation of energy dysfunction caused by the mutant Htt might contribute to the beneficial effects of CGS. Collectively, CGS is a potential drug candidate for the treatment of HD.