Journal
G3-GENES GENOMES GENETICS
Volume 4, Issue 6, Pages 1081-1089Publisher
GENETICS SOCIETY AMERICA
DOI: 10.1534/g3.114.010819
Keywords
reserpine; bupropion; fluoxetine; dopamine receptor; acetylcholine signaling
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Funding
- National Institutes of Health, Office of Research Infrastructure Programs [P40OD010440]
- National Science Foundation [MCB0919413]
- Direct For Biological Sciences
- Div Of Molecular and Cellular Bioscience [1139184] Funding Source: National Science Foundation
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In Caenorhabditis elegans, the dopamine transporter DAT-1 regulates synaptic dopamine (DA) signaling by controlling extracellular DA levels. In dat-1(ok157) animals, DA is not taken back up presynaptically but instead reaches extrasynpatic sites, where it activates the dopamine receptor DOP-3 on choligeneric motor neurons and causes animals to become paralyzed in water. This phenotype is called swimming-induced paralysis (SWIP) and is dependent on datal and dop-3. Upstream regulators of dat-1 and dop-3 have yet to be described in C. elegans. In our previous studies, we defined a role for HLH-17 during dopamine response through its regulation of the dopamine receptors. Here we continue our characterization of the effects of HLH-17 on dopamine signaling. Our results suggest that HLH-17 acts downstream of dopamine synthesis to regulate the expression of dop-3 and dat-1. First, we show that hlh-17 animals display a SWIP phenotype that is consistent with its regulation of dop-3 and dat-1. Second, we show that this behavior is enhanced by treatment with the dopamine reuptake inhibitor, bupropion, in both hlh-17 and dat-1 animals, a result suggesting that SWIP behavior is regulated via a mechanism that is both dependent on and independent of DAT-1. Third, and finally, we show that although the SWIP phenotype of hlh-17 animals is unresponsive to the dopamine agonist, reserpine, and to the antidepressant, fluoxetine, hlh-17 animals are not defective in acetylcholine signaling. Taken together, our work suggests that HLH-17 is required to maintain normal levels of dopamine in the synaptic cleft through its regulation of dop-3 and dat-1.
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