The GTP-binding protein Rhes modulates dopamine signalling in striatal medium spiny neurons

ERRICO F;SANTINI E;MIGLIARINI S;BORGKVIST A;CENTONZE D;NASTI V;CARTA, MANOLO;DE CHIARA V;PROSPERETTI C;SPANO D;HERVE D;PASQUALETTI M;DI LAURO R;FISONE G;USIELLO A.

2008-01-01

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Abstract

Rhes is a small GTP-binding protein prominently localized in the striatum. Previous findings obtained in cell culture systems demonstrated an involvement of Rhes in cAMP/PKA signalling pathway, at a level proximal to the activation of heterotrimeric G-protein complex. However, its role in the striatum has been, so far, only supposed. Here we studied the involvement of Rhes in dopaminergic signalling, by employing mice with a null mutation in the Rhes gene. We demonstrated that the absence of Rhes modulates cAMP/PKA signalling in both striatopallidal and striatonigral projection neurons by increasing Golf protein levels and, in turn, influencing motor responses challenged by dopaminergic agonist/antagonist. Interestingly, we also show that Rhes is required for a correct dopamine-mediated GTP binding, a function mainly associated to stimulation of dopamine D2 receptors. Altogether, our results indicate that Rhes is an important modulator of dopaminergic transmission in the striatum.