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Originally published as Genetics Published Articles Ahead of Print on August 22, 2005.
Genetics, Vol. 172, 885-892, February 2006, Copyright © 2006
doi:10.1534/genetics.103.024869
Fluoxetine-Resistance Genes in Caenorhabditis elegans Function in the Intestine and May Act in Drug Transport
Robert K. M. Choy*,
,1,
John M. Kemner and
James H. Thomas*,,2
* Program in Molecular and Cellular Biology and Department of Genome Sciences, University of Washington, Seattle, Washington 98195
2 Corresponding author: Department of Genome Sciences, Box 357730, University of Washington, Seattle, WA 98195-7360.
E-mail: jht{at}u.washington.edu
Fluoxetine (Prozac) is one of the most widely prescribed pharmaceuticals, yet important aspects of its mechanism of action remain unknown. We previously reported that fluoxetine and related antidepressants induce nose muscle contraction of C. elegans. We also reported the identification and initial characterization of mutations in seven C. elegans genes that cause defects in this response (Nrf, nose resistant to fluoxetine). Here we present genetic evidence that the known nrf genes can be divided into two subgroups that confer sensitivity to fluoxetine-induced nose contraction by distinct pathways. Using both tissue-specific promoters and genetic mosaic analysis, we show that a gene from one of these classes, nrf-6, functions in the intestine to confer fluoxetine sensitivity. Finally, we molecularly identify nrf-5, another gene in the same class. The NRF-5 protein is homologous to a family of secreted lipid-binding proteins with broad ligand specificity. NRF-5 is expressed in the intestine and is likely secreted into the pseudocoelomic fluid, where it could function to transport fluoxetine. One model that explains these findings is that NRF-5 binds fluoxetine and influences its presentation or availability to in vivo targets.
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