Regulator of G‐protein Signaling 6 (RGS6) Modulates Dopamine D2 Autoreceptor Function in Mice

Zili Luo; Katelin E Ahlers-Dannen; Jianqi Yang; Hanna E Stevens; Nandakumar S Narayanan; Rory A Fisher

doi:10.1096/fasebj.2018.32.1_supplement.827.9

The dopaminergic system plays a critical role in the regulation of movement, motivation and cognition and its dysfunction is linked to various neuropsychiatric disorders including Parkinson's Disease. Presynaptic dopamine D2 autoreceptors modulate dopamine signaling in the brain by attenuating its further synthesis and release following the initial synaptic release of dopamine. Consistent with this function, previous studies have demonstrated that pharmacological activation of D2 autoreceptors by quinpirole inhibits presynaptic dopamine release and suppresses locomotion, effects not observed in DAT‐Cre; D2Rfl/fl mice that lack the D2 autoreceptor. RGS6 is a member of the RGS protein family that functions as a GTPase‐activating protein for Gai/o subunits, thereby controlling the intensity and duration of signaling through Gai/o‐linked GPCRs like the D2R. Interestingly, RGS6 is exclusively expressed in dopaminergic neurons of the substantia nigra pars compacta (SNc) of mice and humans, whose loss causes Parkinson's disease, and RGS6 deficient mice exhibit an age‐dependent loss of SNc and striatal dopamine content as well as Parkinson‐like motor dysfunction. Therefore, we hypothesized that SNc dopamine neuron loss in RGS6 deficient mice might result from a lifetime of exaggerated pre‐synaptic D2 autoreceptor signaling culminating in the accumulation of cytotoxic dopamine. To test this hypothesis, we assessed D2 autoreceptor function both in vitro using mouse striatal slices and in vivo. First, we compared the ability of quinpirole to reduce forskolin‐stimulated PKA‐mediated phosphorylation of tyrosine hydroxylase (Ser40) in acute striatal slices derived from WT and RGS6−/− mice. RGS6 deficiency led to exaggerated quinpirole‐mediated inhibition of tyrosine hydroxylase phosphorylation compared to that observed in WT striatal slices. Consistent with these in vitro findings we also found that when 3 mo. WT and RGS6−/− mice, which do not yet display differences in dopamine content, were treated with quinpirole that RGS6−/− mice were more susceptible to quinpirole‐induced suppression of locomotion compared to WT animals despite the mild hyperactivity that has been reported in young RGS6−/− mice. Furthermore, quinpirole also suppressed unsupported rearing in RGS6−/− mice but not WT mice. Together these results demonstrate that RGS6 functions as a critical regulator of D2 autoreceptors in SNc dopamine neurons to modulate dopamine‐dependent motor behaviors. Therefore, loss of RGS6 would be expected to promote hyperactive D2 autoreceptor signaling in these neurons which may underlie their loss in both RGS6−/− mice and humans with Parkinson's. Support or Funding Information NIH CA161882, MJ Fox 11551, Iowa Cardiovascular Interdisciplinary Research Fellowship T32HL007121. This is from the Experimental Biology 2018 Meeting. There is no full text article associated with this published in The FASEB Journal.

Regulator of G‐protein Signaling 6 (RGS6) Modulates Dopamine D2 Autoreceptor Function in Mice

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