Journal
GENETICS
Volume 207, Issue 3, Pages 1023-1039Publisher
GENETICS SOCIETY AMERICA
DOI: 10.1534/genetics.117.300119
Keywords
alcohol; HSF1; optogenetics; protein kinase A; UNC-18
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Funding
- Wellcome Trust [088779/Z/09/Z]
- Biotechnology and Biological Sciences Research Council [BB//K002252/1]
- Medical Research Council Studentship
- National Institutes of Health National Office of Research Infrastructure Program [P40 OD010440]
- BBSRC [BB/K002252/1] Funding Source: UKRI
- MRC [G0801731] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/K002252/1] Funding Source: researchfish
- Medical Research Council [G0801731] Funding Source: researchfish
- Wellcome Trust [088779/Z/09/Z] Funding Source: Wellcome Trust
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Alcohol is a potent pharmacological agent when consumed acutely at sufficient quantities and repeated overuse can lead to addiction and deleterious effects on health. Alcohol is thought to modulate neuronal function through low-affinity interactions with proteins, in particular with membrane channels and receptors. Paradoxically, alcohol acts as both a stimulant and a sedative. The exact molecular mechanisms for the acute effects of ethanol on neurons, as either a stimulant or a sedative, however remain unclear. We investigated the role that the heat shock transcription factor HSF-1 played in determining a stimulatory phenotype of Caenorhabditis elegans in response to physiologically relevant concentrations of ethanol (17 mM; 0.1% v/v). Using genetic techniques, we demonstrate that either RNA interference of hsf-1 or use of an hsf-1(sy441) mutant lacked the enhancement of locomotion in response to acute ethanol exposure evident in wild-type animals. We identify that the requirement for HSF-1 in this phenotype was IL2 neuron-specific and required the downstream expression of the alpha-crystallin ortholog HSP-16.48. Using a combination of pharmacology, optogenetics, and phenotypic analyses we determine that ethanol activates a G(alpha s)-cAMP-protein kinase A signaling pathway in IL2 neurons to stimulate nematode locomotion. We further implicate the phosphorylation of a specific serine residue (Ser322) on the synaptic protein UNC-18 as an end point for the G(alpha s)-dependent signaling pathway. These findings establish and characterize a distinct neurosensory cell signaling pathway that determines the stimulatory action of ethanol and identifies HSP-16.48 and HSF-1 as novel regulators of this pathway.
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