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C. elegans NHX‐2 influences nutrient uptake and insulin signaling
Author(s) -
Pfeiffer Jason R.,
Newell Jennifer,
Sherman Teresa,
Nehrke Keith
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a843-b
Subject(s) - microbiology and biotechnology , biology , rna interference , insulin receptor , signal transduction , insulin , nutrient sensing , cotransporter , biochemistry , gene , endocrinology , chemistry , insulin resistance , rna , sodium , organic chemistry
Disruption of the nhx‐2 gene, which codes for an intestinal Na/H exchanger, leads either to larval arrest or, for those animals that make it through larval development, to an increased lifespan; both effects are mediated through a mechanism resembling starvation. We hypothesized that the proton gradient established by NHX‐2 is functionally coupled to intestinal H+/dipeptide cotransport by OPT‐2. We find that NHX‐2 RNAi causes intracellular acidification and inhibits the uptake of fluorescently labeled dipeptide substrate. We have initiated measurements of luminal pH. We also hypothesized that pHi coordiantes cell growth with nutrient availability. To explore this hypothesis, we performed a two gene loss‐of‐function analysis using nhx‐2 RNAi combined with insulin signaling mutants. We assessed larval development, post‐adult lifespan, and intestinal fat stores. We find that larval arrest is insulin signaling/ daf‐16 dependent, however, lifespan extension requires a daf‐16 independent pathway that utilizes protein kinases associated with insulin signaling. Furthermore, since dauer formation is regulated by nutrient availability, we examined the pHi of the intestine during entry into and recovery from dauer phase. We find that dauer recovery is NHX‐2 dependent and results in a transient acidification of the intestine. Our data suggest a complex regulatory network where pHi influences insulin signaling to coordinate nutrient availability and cell growth. Finally, the initial results from a global RNAi screen for intestinal acidification identified several gene products that act in the mitochondria, suggesting that intestinal pHi may provide a link between caloric restriction, mitochondria function, and insulin signaling.