Abstract
Voltage-gated sodium (Na(v)) channels play a central role in the generation and propagation of action potentials in excitable cells such as neurons and muscles. To determine how the phenotypes of Na(v)-channel mutants are affected by other genes, we performed a forward genetic screen for dominant modifiers of the seizure-prone, gain-of-function Drosophila melanogaster Na(v)-channel mutant, para(Shu) Our analyses using chromosome deficiencies, gene-specific RNA interference, and single-gene mutants revealed that a null allele of glutathione S-transferase S1 (GstS1) dominantly suppresses para(Shu) phenotypes. Reduced GstS1 function also suppressed phenotypes of other seizure-prone Na(v)-channel mutants, para(GEFS+) and para(bss) Notably, para(Shu) mutants expressed 50% less GstS1 than wild-type flies, further supporting the notion that para(Shu) and GstS1 interact functionally. Introduction of a loss-of-function GstS1 mutation into a para(Shu) background led to up- and down-regulation of various genes, with those encoding cytochrome P450 (CYP) enzymes most significantly over-represented in this group. Because GstS1 is a fly ortholog of mammalian hematopoietic prostaglandin D synthase, and in mammals CYPs are involved in the oxygenation of polyunsaturated fatty acids including prostaglandins, our results raise the intriguing possibility that bioactive lipids play a role in GstS1-mediated suppression of para(Shu) phenotypes.