Academic journal article Genetics

Receptors and Other Signaling Proteins Required for Serotonin Control of Locomotion in Caenorhabditis Elegans

Academic journal article Genetics

Receptors and Other Signaling Proteins Required for Serotonin Control of Locomotion in Caenorhabditis Elegans

Article excerpt

ABSTRACT A better understanding of the molecular mechanisms of signaling by the neurotransmitter serotonin is required to assess the hypothesis that defects in serotonin signaling underlie depression in humans. Caenorhabditis elegans uses serotonin as a neurotransmitter to regulate locomotion, providing a genetic system to analyze serotonin signaling. From large-scale genetic screens we identified 36 mutants of C. elegans in which serotonin fails to have its normal effect of slowing locomotion, and we molecularly identified eight genes affected by 19 of the mutations. Two of the genes encode the serotonin-gated ion channel MOD-1 and the G-protein-coupled serotonin receptor SER-4. mod-1 is expressed in the neurons and muscles that directly control locomotion, while ser-4 is expressed in an almost entirely non-overlapping set of sensory and interneurons. The cells expressing the two receptors are largely not direct postsynaptic targets of serotonergic neurons. We analyzed animals lacking or overexpressing the receptors in various combinations using several assays for serotonin response. We found that the two receptors act in parallel to affect locomotion. Our results show that serotonin functions as an extrasynaptic signal that independently activates multiple receptors at a distance from its release sites and identify at least six additional proteins that appear to act with serotonin receptors to mediate serotonin response.

DEPRESSION is hypothesized to involve dysfunction of the neurotransmitter serotonin (Cowen 2008). Understanding the molecular mechanism of serotonin signaling is complicated by the fact that the human brain expresses 14 types of serotonin receptors, one of which is a serotonin-gated ion channel, and the rest of which are G-protein-coupled receptors (Millan et al. 2008). An additional challenge to understanding serotonin signaling is the fact that serotonin can act locally at synapses where it is released or diffuse away and act at distant receptors. While classical neurotransmitters such as GABA and glutamate appear to function mainly locally at synapses, serotonin can diffuse several microns from its release sites at concentrations sufficient to activate its receptors (Bunin and Wightman 1998). Furthermore, serotonin receptors are often localized at nonsynaptic sites (Kia et al. 1996). These observations suggest that serotonin might act predominantly as an extrasynaptic signal to activate several receptor types on cells distant from its release sites and that the combined action of these several receptors somehow coordinates appropriate responses to serotonin. The details of how such action might occur remain unclear.

Caenorhabditis elegans uses serotonin as a neurotransmitter (Horvitz et al. 1982; Chase and Koelle 2007) and provides a model system with the potential to make important contributions to the study of serotonin signaling. First, C. elegans allows the use of forward genetic screens to identify the proteins beyond serotonin receptors that mediate serotonin response. Second, the known synaptic wiring of the C. elegans nervous system (White et al. 1986) provides the opportunity to directly test whether serotonin acts at synapses or extrasynaptically.

Previous studies of C. elegans have shown that, of the precisely 302 neurons found in an adult hermaphrodite, the NSM, HSN, ADF, VC4/5, AIM, and RIH neurons contain serotonin, although the AIM, RIH, and possibly also the VC4/5 neurons do not synthesize serotonin themselves but rather take up serotonin made by the other neurons (Horvitz et al. 1982; Sawin et al. 2000; Jafari et al. 2011). Animals with mutations in the enzymes that synthesize serotonin or in which the NSMs have been ablated are defective for the strong reduction in locomotion behavior, known as enhanced slowing, that occurs when food-deprived animals encounter food (Sawin et al. 2000). This observation suggests that the NSMs release serotonin to slow locomotion. While enhanced slowing is only one of several behaviors known to be controlled by serotonin in C. …

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