Abstract
Ethanol is a widely used beverage and abused drug. Alcoholism causes severe damage to human health and creates serious social problems. Understanding the mechanisms underlying ethanol actions is important for the development of effective therapies. Alcohol has a wide spectrum of effects on physiological activities and behaviours, from sensitization to sedation and even intoxication with increasing concentrations. Animals develop tolerance to ethanol. However, the underlying mechanisms are not well understood. In Caenorhabditis elegans, NPR-1 negatively regulates the development of acute tolerance to ethanol. Here, using in vivo Ca2+ imaging, behavioural tests and chemogenetic manipulation, we show that the soluble guanylate cyclase complex GCY-35/GCY-36—TAX-2/TAX-4 signalling pathway in O2 sensory neurons positively regulates acute functional tolerance in npr-1 worms.
Highlights
GCY-35/GCY-36—TAX-2/TAX-4 signalling pathway is involved in acute functional ethanol tolerance in npr-1 worms
Our results showed that almost all single gene mutants of gyc-35, gcy-36, tax-2 and tax-4 exhibited ethanol sensitivity and acute functional ethanol tolerance similar to N2 worms (Supplementary Fig. 1). npr-1(ad609) showed increased acute functional tolerance (Fig. 1A, Supplementary Movies 1–4) as reported previously[23]
Similar to npr-1(ad609); gcy-35(ok769) double mutant, npr-1(ad609); gcy-36(db42) double mutant showed a reduced relative speed compared with that in npr1(ad609) and similar to that in N2 worms (Fig. 1B). These results suggest that gcy-35/gcy-36 is involved in acute ethanol tolerance in C. elegans
Summary
Multiple genes that control acute sensitivity to ethanol have been identified in C. elegans[7,20]. It is still important to identify novel genes and signalling pathways that are involved in acute ethanol tolerance. Due to feasible genetic and neuronal manipulations, rich genetic tools and vertebrate neuronal protein homologues, the nematode C. elegans is a useful model animal to identify novel ethanol target sites and molecular bases for ethanol tolerance. Using in vivo Ca2+ imaging, behavioural tests and chemogenetic experiments, we present evidence that suggests that the GCY-35/GCY-36—TAX-2/TAX4 signalling pathway in O2 sensory neurons URX, AQR and PQR, mediates the ethanol excitatory effect on these neurons and functions in acute functional ethanol tolerance in npr-1 animals
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