Fig. 4.
Model of RGS6’s role in regulation of SNc D2 autoreceptor signaling. RGS6 in SNc DA neurons inhibits D2-autoreceptor signaling to promote proper DA homeostasis and neurotransmission as well as prevent aberrant α-synuclein accumulation. By inhibiting SNc D2-autoreceptor-Gαi/o signaling, RGS6 promotes DA packaging/release by preventing Vmat2 downregulation and DAT upregulation/activation. In addition, RGS6 inhibition of D2-autoreceptor-Gαi/o signaling promotes cAMP/PKA signaling, increasing DA synthesis (TH phosphorylation) and suppressing α-synuclein expression. β-agonists, which have been shown to reduce PD incidence work in a similar fashion. In contrast, RGS6 loss, as seen in the RGS6−/− mouse model, disinhibits SNc D2-autoreceptor-Gαi/o signaling, reducing cAMP-mediated DA synthesis and increasing α-synuclein accumulation. Furthermore, RGS6 loss is associated with cytotoxic DA (DOPAL) accumulation due to SNc D2-autoreceptor-Gαi/o–mediated Vmat2 downregulation and DAT upregulation. This figure depicts SNc DA neurons (blue) synapsing on GABAergic D1R- and D2R-containing MSNs (red). Gαi/o-coupled receptors are red and Gαs-coupled receptors are green. DOPAL, 3,4-dihydroxyphenylacetaldehyde; MSN, medium spiny neuron; TH, tyrosine hydroxylase.