Abstract
Dopamine signaling modulates voluntary movement and reward-driven behaviors by acting through G protein-coupled receptors in striatal neurons, and defects in dopamine signaling underlie Parkinson's disease and drug addiction. Despite the importance of understanding how dopamine modifies the activity of striatal neurons to control basal ganglia output, the molecular mechanisms that control dopamine signaling remain largely unclear. Dopamine signaling also controls locomotion behavior in Caenorhabditis elegans. To better understand how dopamine acts in the brain we performed a large-scale dsRNA interference screen in C. elegans for genes required for endogenous dopamine signaling and identified six genes (eat-16, rsbp-1, unc-43, flp-1, grk-1, and cat-1) required for dopamine-mediated behavior. We then used a combination of mutant analysis and cell-specific transgenic rescue experiments to investigate the functional interaction between the proteins encoded by two of these genes, eat-16 and rsbp-1, within single cell types and to examine their role in the modulation of dopamine receptor signaling. We found that EAT-16 and RSBP-1 act together to modulate dopamine signaling and that while they are coexpressed with both D1-like and D2-like dopamine receptors, they do not modulate D2 receptor signaling. Instead, EAT-16 and RSBP-1 act together to selectively inhibit D1 dopamine receptor signaling in cholinergic motor neurons to modulate locomotion behavior.
Highlights
Dopamine (DA) modulates neural activity by acting through two classes of G protein-coupled receptors
As the ability of animals to slow in response to food is absolutely dependent upon endogenous DA signaling, these results indicate that RSBP-1 is required for dopamine signaling in vivo and again suggest that RSBP-1 is not acting as an inhibitor of D2-like DOP-3 receptor signaling as both rsbp-1 and dop-3 mutants fail to slow in response to food
This screen resulted in the identification of six genes, unc-43, flp-1, grk-1, cat-1, eat-16, and rsbp-1 that were required for the execution of DAmediated behaviors. unc-43 encodes the homolog of calcium/ calmodulin-dependent protein kinase (CamKII)
Summary
Dopamine (DA) modulates neural activity by acting through two classes of G protein-coupled receptors. These receptors are expressed in many regions of the brain including the prefrontal cortex where they can affect short-term working memory and in the basal ganglia where they affect motor and reward behaviors [1,2,3,4]. Coupling of DA receptors to specific G protein subunits is not strict as each receptor can act through several different a subunits depending on the cell type in which the receptor is expressed and a subunit availability [12,13,14]
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