Johnson, James R ORCID: 0000-0002-8849-0993, Edwards, Mark R, Davies, Huw, Newman, Daniel, Holden, Whitney, Jenkins, Rosalind E, Burgoyne, Robert D ORCID: 0000-0002-9219-0387, Lucas, Robert J and Barclay, Jeff W
(2017)
Ethanol Stimulates Locomotion via a G(alpha s)-Signaling Pathway in IL2 Neurons in Caenorhabditis elegans.
GENETICS, 207 (3).
pp. 1023-1039.
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FINAL_Johnson et al.pdf - Author Accepted Manuscript Download (6MB) |
Abstract
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 α-crystallin ortholog HSP-16.48. Using a combination of pharmacology, optogenetics, and phenotypic analyses we determine that ethanol activates a Gαs-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 Gαs-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.
Item Type: | Article |
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Uncontrolled Keywords: | alcohol, HSF1, optogenetics, protein kinase A, UNC-18 |
Depositing User: | Symplectic Admin |
Date Deposited: | 06 Nov 2017 16:34 |
Last Modified: | 19 Jan 2023 06:52 |
DOI: | 10.1534/genetics.117.300119 |
Related URLs: | |
URI: | https://livrepository.liverpool.ac.uk/id/eprint/3010641 |