Natural variation in protein kinase D modifies alcohol sensitivity in Caenorhabditis elegans

Differences in naive alcohol sensitivity between individuals are a strong predictor of later life alcohol use disorders (AUD). However, the genetic bases for alcohol sensitivity (beyond ethanol metabolism) and pharmacological approaches to modulate alcohol sensitivity remain poorly understood. We used a high-throughput behavioral screen to measure acute behavioral sensitivity to alcohol, a model of intoxication, in a genetically diverse set of over 150 wild strains of the nematode Caenorhabditis elegans. We performed a genome-wide association study to identify loci that underlie natural variation in alcohol sensitivity. We identified five quantitative trait loci (QTL) and further show that variants in the C. elegans ortholog of protein kinase D, dkf-2, likely underlie the chromosome V QTL. We found that resistance to intoxication was conferred by dkf-2 loss-of-function mutations as well as partly by a PKD inhibitor in a dkf-2-dependent manner. Protein kinase D might represent a conserved, druggable target to modify alcohol sensitivity with application towards AUD. Significance statementHere, we identify a novel role for protein kinase D (dkf-2) in C. elegans alcohol sensitivity. PKD, like protein kinase C, might represent a newly discovered druggable target to modify alcohol response. Identifying causal variants in genes of the remaining loci will likewise provide new insights into the genetic basis of variation in naive alcohol sensitivity in C. elegans and other organisms.