title: RasGRP1 promotes amphetamine-induced motor behavior through a Rhes interaction network ("Rhesactome") in the striatum.
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.
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Neelam
authors.initials: N
authors.lastname: Shahani
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Supriya
authors.initials: S
authors.lastname: Swarnkar
authors.affiliation: Harriet L. Wilkes Honors College, Florida Atlantic University, Jupiter, FL 33458, USA.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Giovinazzo
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Jenny
authors.initials: J
authors.lastname: Morgenweck
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Bohn
authors.affiliation: Proteomics Core, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Catherina
authors.initials: C
authors.lastname: Scharager-Tapia
authors.affiliation: Informatics Core, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Pascal
authors.affiliation: Proteomics Core, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Pablo
authors.initials: P
authors.lastname: Martinez-Acedo
authors.affiliation: Department of Statistics, University of Florida, Gainesville, FL 32611, USA.
authors.forename: Kshitij
authors.initials: K
authors.lastname: Khare
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA. ssubrama@scripps.edu.
authors.forename: Srinivasa
authors.initials: S
authors.lastname: Subramaniam
mesh_terms: D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008124:Locomotion / Q000187:drug effects*; D008817:Mice, Mutant Strains; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C112278:Rasgrp1 protein, mouse; D000661:Amphetamine; D019204:GTP-Binding Proteins; C488189:Rasd2 protein, mouse