Mutations in the Caenorhabditis elegans serotonin reuptake transporter MOD-5 reveal serotonin-dependent and -independent activities of fluoxetine.
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.
Ranganathan
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Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Sawin
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ER
Trent
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Horvitz
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HR
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D002478:Cells, Cultured; D003001:Cloning, Molecular; D004252:DNA Mutational Analysis; D004357:Drug Synergism; D005247:Feeding Behavior / Q000187:drug effects / Q000502:physiology; D005473:Fluoxetine / Q000494:pharmacology*; D005816:Genetic Complementation Test; D015801:Helminth Proteins / Q000235:genetics / Q000378:metabolism; D007834:Lasers; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism*; D026901:Membrane Transport Proteins; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009046:Motor Neurons / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D016296:Mutagenesis; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D012701:Serotonin / Q000378:metabolism* / Q000493:pharmacokinetics; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D005473:Fluoxetine; D015801:Helminth Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C493229:mod-5 protein, C elegans