Research ArticleBiochemistry

RasGRP1 promotes amphetamine-induced motor behavior through a Rhes interaction network (“Rhesactome”) in the striatum

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Sci. Signal.  15 Nov 2016:
Vol. 9, Issue 454, pp. ra111
DOI: 10.1126/scisignal.aaf6670

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Rhes networks in motor control

Drugs like amphetamine, which stimulates the release of both norepinephrine and dopamine, enhance locomotor activity, which could be beneficial in various neurological and psychological disorders characterized by impaired dopamine signaling in the striatum, such as Huntington’s disease and Parkinson’s disease. The striatal GTPase Rhes suppresses amphetamine-induced locomotion in mice and is implicated in Huntington’s disease. Shahani et al. identified protein interaction networks centered on Rhes in mice. Both amphetamine and the guanine exchange factor RasGRP1 altered the proteins with which Rhes interacted, including several that are associated with various neurological diseases. The findings have implications for understanding the molecular underpinnings of amphetamine’s locomotor effects, which may enable development of better therapeutics.

Abstract

The striatum of the brain coordinates motor function. Dopamine-related drugs may be therapeutic to patients with striatal neurodegeneration, such as Huntington’s disease (HD) and Parkinson’s disease (PD), but these drugs have unwanted side effects. In addition to stimulating the release of norepinephrine, amphetamines, which are used for narcolepsy and attention-deficit/hyperactivity disorder (ADHD), trigger dopamine release in the striatum. The guanosine triphosphatase Ras homolog enriched in the striatum (Rhes) inhibits dopaminergic signaling in the striatum, is implicated in HD and L-dopa–induced dyskinesia, and has a role in striatal motor control. We found that the guanine nucleotide exchange factor RasGRP1 inhibited Rhes-mediated control of striatal motor activity in mice. RasGRP1 stabilized Rhes, increasing its synaptic accumulation in the striatum. Whereas partially Rhes-deficient (Rhes+/−) mice had an enhanced locomotor response to amphetamine, this phenotype was attenuated by coincident depletion of RasGRP1. By proteomic analysis of striatal lysates from Rhes-heterozygous mice with wild-type or partial or complete knockout of Rasgrp1, we identified a diverse set of Rhes-interacting proteins, the “Rhesactome,” and determined that RasGRP1 affected the composition of the amphetamine-induced Rhesactome, which included PDE2A (phosphodiesterase 2A; a protein associated with major depressive disorder), LRRC7 (leucine-rich repeat–containing 7; a protein associated with bipolar disorder and ADHD), and DLG2 (discs large homolog 2; a protein associated with chronic pain). Thus, this Rhes network provides insight into striatal effects of amphetamine and may aid the development of strategies to treat various neurological and psychological disorders associated with the striatal dysfunction.

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