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Aberrant amplification of A 2A receptor signaling in striatal cells expressing mutant huntingtin
Author(s) -
Varani Katia,
Rigamonti Dorotea,
Sipione Simonetta,
Camurri Alessandra,
Borea Pier Andrea,
Cattabeni Flaminio,
Abbracchio Maria P.,
Cattaneo Elena
Publication year - 2001
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.00-0730fje
Subject(s) - huntingtin , mutant , microbiology and biotechnology , receptor , chemistry , biology , genetics , gene
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 A 2A and D 2 receptors, which stimulate and inhibit adenylyl cyclase, respectively. In this study we analyzed the possibility of an involvement of the A 2A 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 A 2A receptor ligand 3 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. 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 A 2A 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 A 2A 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 A 2A 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.