To identify mutants that might perceive a constitutive state of food deprivation, we screened for mutants that behave as if they had been food-deprived when well fed. Well-fed C. elegans animals that encounter a bacterial lawn slow their locomotion in the basal slowing response. Acutely food-deprived animals slow more upon entering a bacterial lawn, in the enhanced slowing response. Deletion of
mod-5, which encodes a serotonin reuptake transporter, confers increased
slowing on food in both conditions. Using a
mod-5(
n3314) deletion background, we screened for
mutants that exhibited enhanced slowing in the well-fed state.
From this screen we isolated an allele of
mrp-1 (multidrug resistance protein family), a member of a large family of ABC transporters.
mrp-1 is the C. elegans ortholog of the human sulfonylurea receptor SUR1, which attenuates ATP-dependent inward-rectifying potassium currents in pancreatic beta cells, thus stimulating insulin secretion. The SUR1/KIR6.x complex is sensitive to changing ATP/ADP levels and is thought to be an important component in glucose homeostasis in many cell types, including
neurons.
daf-2 encodes a C. elegans insulin-like receptor. Like
mrp-1 mutants,
daf-2(
e1370) mutants display a constitutive enhanced slowing response in a
mod-5(
n3314) background, consistent with the hypothesis that both mutants perceive a constitutively food-deprived state. We propose that, analogous to the function of SUR1 in humans,
mrp-1 may act as a metabolic sensor in the insulin signaling pathway in C. elegans.
Tangential to this study, we discovered that wild strain CB4856 has a greatly reduced enhanced slowing response and that this defect maps to the X chromosome. Work by DeBono et al. (Cell 94: 679-689, 1998) led us to identify
npr-1 as the gene responsible for this modulation defect.
npr-1 encodes a putative neuropeptide Y-like receptor. The mammalian neuropeptide Y receptor functions in energy homeostasis to stimulate increased food consumption in response to a deficit in
stored energy. We postulate that
npr-1 acts similarly in C. elegans and is involved signaling a food-deprived state. We are currently attempting to identify NPR-1 ligands involved in enhanced slowing
and the circuit in which
npr-1 acts in the enhanced slowing response.