Abstract
Rhes is one of the most interesting genes regulated by thyroid hormones that, through the inhibition of the striatal cAMP/PKA pathway, acts as a modulator of dopamine neurotransmission. Rhes mRNA is expressed at high levels in the dorsal striatum, with a medial-to-lateral expression gradient reflecting that of both dopamine D2 and adenosine A2A receptors. Rhes transcript is also present in the hippocampus, cerebral cortex, olfactory tubercle and bulb, substantia nigra pars compacta (SNc) and ventral tegmental area of the rodent brain. In line with Rhes-dependent regulation of dopaminergic transmission, data showed that lack of Rhes enhanced cocaine- and amphetamine-induced motor stimulation in mice. Previous studies showed that pharmacological depletion of dopamine significantly reduces Rhes mRNA levels in rodents, non-human primates and Parkinson’s disease (PD) patients, suggesting a link between dopaminergic innervation and physiological Rhes mRNA expression. Rhes protein binds to and activates striatal mTORC1, and modulates L-DOPA-induced dyskinesia in PD rodent models. Finally, Rhes is involved in the survival of mouse midbrain dopaminergic neurons of SNc, thus pointing towards a Rhes-dependent modulation of autophagy and mitophagy processes, and encouraging further investigations about mechanisms underlying dysfunctions of the nigrostriatal system.
Highlights
Since its early identification by Sutcliff’s group [1], the Ras-related family member, Ras homolog enriched in striatum (Rhes), has been attracting many researchers who work on different topics, thanks to the pleiotropic actions of this highly striatal-enriched protein, which make it a suitable molecular adaptor, under both physiological and pathological conditions
In this line, taking a cue from what we have discussed in the present review, we can draw a sort of general picture about Rhes functions
Rhes expression is developmentally modulated by thyroid hormone, showing increasing mRNA levels between the perinatal phases in rodents, and reaching the highest amount in adulthood [7,13], which entails its potential involvement in alterations of relevance to thyroid hormone-dependent neurological disorders, including cretinism
Summary
Together with Dexras, Rhes differs from other cognate members for having peculiar N- and C-terminal domains [3,4]. In this respect, while the N-terminal sequence, encompassing 1–18 amino acids, is likely to have the binding motif for the deubiquitinating enzyme, the C-terminal cationic domain interacts with Gβ1 , Gβ2 and Gβ3 subunits of heterotrimeric G proteins [5], and contains a well-conserved CAAX motif that, following the enzymatic post-translational modification (farnesylation), is able to translocate this small protein to the plasma membrane [6,7,8]
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