RasGRP1 promotes amphetamine-induced motor behavior through a Rhes interaction network ('Rhesactome') in the striatum
| Autor: | Srinivasa Subramaniam, Laura M. Bohn, Neelam Shahani, Kshitij Khare, Vincenzo Giovinazzo, Bruce D. Pascal, Pablo Martínez-Acedo, Supriya Swarnkar, Jenny Morgenweck, Catherina Scharager-Tapia |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Striatum Biochemistry Article 03 medical and health sciences Norepinephrine 0302 clinical medicine GTP-Binding Proteins Dopamine Internal medicine medicine Animals Guanine Nucleotide Exchange Factors Humans Amphetamine Molecular Biology Behavior Animal Chemistry Neurodegeneration Dopaminergic Cell Biology medicine.disease Mice Mutant Strains Rats HEK293 Cells 030104 developmental biology Endocrinology nervous system Guanine nucleotide exchange factor Locomotion 030217 neurology & neurosurgery Signal Transduction Narcolepsy medicine.drug |
| Zdroj: | Science Signaling. 9 |
| ISSN: | 1937-9145 1945-0877 |
| DOI: | 10.1126/scisignal.aaf6670 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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