Fluorescence imaging of a worm carrying integrated transgenes that express green fluorescent protein from the dop-1 promoter and red fluorescent protein from the dop-3 promoter. Image courtesy of D. Chase, Yale University, USA.

In mammals and other animals, dopamine receptors can be split into two groups — D1-like and D2-like. Writing in Nature Neuroscience, Chase et al. describe a genetic analysis of dopamine signalling in the worm Caenorhabiditis elegans that sheds light on the antagonistic properties of these two types of receptor.

There is strong evidence from mammalian studies that signalling through D1- and D2-like dopamine receptors has opposing effects on locomotor behaviour, and that the two types of receptor can signal through different neuronal G proteins. To delve deeper into the mechanisms of dopaminergic signalling, the authors turned to the genetic tools that are available for C. elegans.

In a search of the C. elegans genome, using the known D1-like receptor DOP-1 and D2-like receptor DOP-2 for comparison, the authors identified a new D2-like dopamine receptor, DOP-3. Worms in which the dop-3 gene was deleted showed a reduced 'basal slowing response' — the slowing of locomotion that is normally caused when a worm encounters a bacterial lawn, and which is known to be controlled by dopamine signalling. By contrast, dop-1 or dop-2 mutants showed a normal basal slowing response. dop-3 mutants were also resistant to the paralytic effects of high concentrations of exogenous dopamine, whereas dop-1 or dop-2 mutants showed no such resistance. However, double mutants for both dop-1 and dop-3 showed a near-normal response in both cases, indicating that DOP-1 signalling antagonizes DOP-3.

To investigate the cellular basis for these effects, the authors looked at the expression of the dopamine receptors in C. elegans. Although the expression patterns of DOP-1 and DOP-3 did not initially seem to overlap, closer inspection revealed that the cholinergic motor neurons of the ventral cord expressed dop-1 strongly and dop-3 more weakly. Experiments in which expression of dop-1 or dop-3 was restored specifically in these motor neurons in mutant worms showed that the effects of the two receptors on locomotion were mediated by these neurons, showing that the antagonistic effects of D1-like and D2-like receptors can occur in the same cell.

What signalling pathways are responsible for these effects? In a screen for other dopamine-resistant mutants, Chase et al. found nine mutations in four genes, each of which encodes a neuronal G-protein signalling molecule. These signalling molecules were components of two opposing signalling pathways that have been characterized in C. elegans and that are conserved in mammals. Mutations that either increased signalling through the Gαq pathway or decreased signalling through the Gαo pathway resulted in dopamine resistance. These results and others fit a model in which DOP-3 signals through Gαo to inhibit locomotion, and DOP-1 antagonizes this effect by signalling though Gαq.

Dopamine signalling in worms shows striking parallels with the dopamine system in mammals. In both types of animal, D1- and D2-like receptors are expressed at different levels in the same neurons, and can have opposing effects on behaviour. As in worms, D1 receptors in mammals can activate Gαq signalling, and D2 receptors can activate Gαo signalling, although it has not been previously shown that these pathways mediate their antagonistic effects. Moreover, dopamine in both worms and mammals can act extrasynaptically as a neurohormone. If these parallels hold true for other details of dopamine signalling, results from studies of C. elegans could give important insights into how mammalian dopamine receptors function.