Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We isolated two mutants defective in the uptake of exogenous serotonin (5-HT) into the neurosecretory motor neurons of Caenorhabditis elegans. These mutants were hypersensitive to exogenous 5-HT and hyper-responsive in the experience-dependent enhanced slowing response to food modulated by 5-HT. The two allelic mutations defined the gene mod-5 (modulation of locomotion defective), which encodes the only serotonin reuptake transporter (SERT) in C. elegans. The selective serotonin reuptake inhibitor fluoxetine (Prozac) potentiated the enhanced slowing response, and this potentiation required mod-5 function, establishing a 5-HT- and SERT-dependent behavioral effect of fluoxetine in C. elegans. By contrast, other responses of C. elegans to fluoxetine were independent of MOD-5 SERT and 5-HT. Further analysis of the MOD-5-independent behavioral effects of fluoxetine could lead to the identification of novel targets of fluoxetine and could facilitate the development of more specific human pharmaceuticals.
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PMID:Mutations in the Caenorhabditis elegans serotonin reuptake transporter MOD-5 reveal serotonin-dependent and -independent activities of fluoxetine. 1148 10

Drugs that target the serotonergic system are the most commonly prescribed therapeutic agents and are used for treatment of a wide range of behavioral and neurological disorders. However, the mechanism of the drug action remain a conjecture. Here, we dissect the genetic targets of serotonin (5HT), the selective 5HT reuptake inhibitor (SSRI) fluoxetine (Prozac), the tricyclic antidepressant imipramine, and dopamine. Using the well-established serotonergic response in C. elegans egg-laying behavior as a paradigm, we show that action of fluoxetine and imipramine at the 5HT reuptake transporter (SERT) and at 5HT receptors are separable mechanisms. Even mutants completely lacking 5HT or SERT can partially respond to fluoxetine and imipramine. Furthermore, distinct mechanisms for each drug can be recognized to mediate these responses. Deletion of SER-1, a 5HT1 receptor, abolishes the response to 5HT but has only a minor effect on the response to imipramine and no effect on the response to fluoxetine. In contrast, deletion of SER-4, a 5HT2 receptor, confers significant resistance to imipramine while leaving the responses to 5HT or fluoxetine intact. Further, fluoxetine can stimulate egg laying via the Gq protein EGL-30, independent of SER-1, SER-4, or 5HT. We also show that dopamine antagonizes the 5HT action via the 5HT-gated ion channel MOD-1 signaling, suggesting that this channel activity couples 5HT and dopamine signaling. These results suggest that the actions of these drugs at specific receptor subtypes could determine their therapeutic efficacy. SSRIs and tricyclic antidepressants may regulate 5HT outputs independently of synaptic levels of 5HT.
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PMID:Serotonin (5HT), fluoxetine, imipramine and dopamine target distinct 5HT receptor signaling to modulate Caenorhabditis elegans egg-laying behavior. 1565 17