West Coast Worm Meeting Abstracts - Caenorhabditis elegans ...

West Coast Worm Meeting 2000
HAPPY WORMS: FURTHER CHARACTERIZATION OF
FLUOXETINE (PROZAC) RESISTANT MUTANTS
Robert K.M. Choy 1,2 , James H. Thomas 2,3
1Program in Molecular and Cellular Biology, Box 357360, University of Washington, Seattle, WA
98195-7360
2rchoy@genetics.washington.edu
3Department of Genetics, Box 357360, University of Washington, Seattle, WA 98195-7360
Although over 20 million people have taken fluoxetine for a wide range of mental disorders, its molecular
mechanism of action remains unproven. Fluoxetine is a member of the selective serotonin reuptake
inhibitor (SSRI) class of antidepressants, which inhibit the presynaptic serotonin reuptake transporter.
However, it is still unclear whether this inhibition is responsible for their antidepressant action.
Furthermore, the targets responsible for the various side-effects of SSRIs are poorly characterized.
We previously reported that in C. elegans, SSRIs induce contraction of nose and body-wall muscles by
acting on a non-serotonergic target. We also reported the isolation and characterization of several
mutants that are nose resistant to fluoxetine (Nrf). These mutants are cross-resistant to other SSRIs, but
are fully sensitive to several other drugs that also induce nose muscle contraction. Therefore, these Nrf
mutations may identify novel genes relevant to antidepressant action.
Mutations in three of the Nrf genes (nrf-5, nrf-6 and ndg-4) have a common secondary phenotype of
producing pale eggs (Peg). These mutants are defective in yolk transport and accumulate yolk in the
pseudocoelomic space. nrf-6 and ndg-4 both encode homologous transmembrane proteins and define a
novel gene family of several dozen members in C. elegans and Drosophila. By a combination of mosaic
analysis and tissue specific promoters, we have found that nrf-6 function is required in the intestine for
both fluoxetine-induced nose contraction and yolk transport. We have also cloned nrf-5 and found that it
is homologous to the mammalian BPI/CETP family of secreted lipid binding proteins. One possibility is
that these genes are involved in a novel aspect of antidepressant transport. Alternatively, they may
mediate some aspect of lipid metabolism that is required for antidepressant-induced nose muscle
contraction.
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