Lipid Environment Modulates the Development of Acute Tolerance to Ethanol in Caenorhabditis elegans

Bettinger, Jill C.; Leung, Kapo; Bolling, Mia H.; Goldsmith, Andrew D.; Davies, Andrew G.

doi:10.1371/journal.pone.0035192

Cited by 39 publications

(49 citation statements)

References 42 publications

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“…Although we do not yet know the relevant targets of SWI/SNF regulation for ethanol-response behaviors, we have identified several genes that regulate initial sensitivity and AFT in worms that are excellent candidates for regulation by SWI/SNF, including the large conductance voltage and calcium sensitive potassium (BK) channel and genes that regulate lipid metabolism and utilization in the animal (23,24,46). Variation in SWI/SNF components may influence these and/or other as-yet-unidentified downstream mediators of the behavioral response to ethanol.…”

Section: Discussionmentioning

confidence: 99%

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SWI/SNF chromatin remodeling regulates alcohol response behaviors in Caenorhabditis elegans and is associated with alcohol dependence in humans

Mathies¹,

Blackwell²,

Austin³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Alcohol abuse is a widespread and serious problem. Understanding the factors that influence the likelihood of abuse is important for the development of effective therapies. There are both genetic and environmental influences on the development of abuse, but it has been difficult to identify specific liability factors, in part because of both the complex genetic architecture of liability and the influences of environmental stimuli on the expression of that genetic liability. Epigenetic modification of gene expression can underlie both genetic and environmentally sensitive variation in expression, and epigenetic regulation has been implicated in the progression to addiction. Here, we identify a role for the switching defective/sucrose nonfermenting (SWI/SNF) chromatin-remodeling complex in regulating the behavioral response to alcohol in the nematode Caenorhabditis elegans. We found that SWI/SNF components are required in adults for the normal behavioral response to ethanol and that different SWI/SNF complexes regulate different aspects of the acute response to ethanol. We showed that the SWI/SNF subunits SWSN-9 and SWSN-7 are required in neurons and muscle for the development of acute functional tolerance to ethanol. Examination of the members of the SWI/SNF complex for association with a diagnosis of alcohol dependence in a human population identified allelic variation in a member of the SWI/SNF complex, suggesting that variation in the regulation of SWI/SNF targets may influence the propensity to develop abuse disorders. Together, these data strongly implicate the chromatin remodeling associated with SWI/SNF complex members in the behavioral responses to alcohol across phyla.SWI/SNF | alcohol | C. elegans | chromatin remodeling | GWAS

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Section: Discussionmentioning

confidence: 99%

“…The molecular effects of ethanol on the nervous system are conserved functionally and molecularly in mammals and in worms (18)(19)(20)(21)(22)(23)(24).…”

Section: Significancementioning

confidence: 99%

SWI/SNF chromatin remodeling regulates alcohol response behaviors in Caenorhabditis elegans and is associated with alcohol dependence in humans

Mathies¹,

Blackwell²,

Austin³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Mutations in multiple genes have previously been shown to generate altered phenotypes compared to wild-type animals upon treatment with ethanol (Davies et al 2003(Davies et al , 2004Kayser et al 2003;Kapfhamer et al 2008;Graham et al 2009;Speca et al 2010;Bettinger et al 2012;Bhandari et al 2012;Jee et al 2013;Raabe et al 2014). We examined two of these genes that have robust mutant ethanol response phenotypes, slo-1 and npr-1.…”

Section: Ehc Is Distinct From Previously Identified Ethanol Responsesmentioning

confidence: 99%

“…Ethanol also produces disinhibition of certain crawling behaviors that would normally be inhibited in a liquid environment (Topper et al 2014). Acute functional tolerance, which is unrelated to metabolism of the drug, develops rapidly to the effects of ethanol on the speed of locomotion (Davies et al 2004;Bettinger et al 2012;Raabe et al 2014). Longer ethanol exposures followed by removal from the drug can lead to withdrawal-related phenotypes (Davies et al 2004;Mitchell et al 2010).…”

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confidence: 99%

A Novel Cholinergic Action of Alcohol and the Development of Tolerance to That Effect inCaenorhabditis elegans

et al. 2014

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Understanding the genes and mechanisms involved in acute alcohol responses has the potential to allow us to predict an individual's predisposition to developing an alcohol use disorder. To better understand the molecular pathways involved in the activating effects of alcohol and the acute functional tolerance that can develop to such effects, we characterized a novel ethanolinduced hypercontraction response displayed by Caenorhabditis elegans. We compared body size of animals prior to and during ethanol treatment and showed that acute exposure to ethanol produced a concentration-dependent decrease in size followed by recovery to their untreated size by 40 min despite continuous treatment. An increase in cholinergic signaling, leading to muscle hypercontraction, is implicated in this effect because pretreatment with mecamylamine, a nicotinic acetylcholine receptor (nAChR) antagonist, blocked ethanol-induced hypercontraction, as did mutations causing defects in cholinergic signaling (cha-1 and unc-17). Analysis of mutations affecting specific subunits of nAChRs excluded a role for the ACR-2R, the ACR-16R, and the levamisole-sensitive AChR and indicated that this excitation effect is dependent on an uncharacterized nAChR that contains the UNC-63 a-subunit. We performed a forward genetic screen and identified eg200, a mutation that affects a conserved glycine in EAT-6, the a-subunit of the Na + /K + ATPase. The eat-6(eg200) mutant fails to develop tolerance to ethanol-induced hypercontraction and remains contracted for at least 3 hr of continuous ethanol exposure. These data suggest that cholinergic signaling through a specific a-subunit-containing nAChR is involved in ethanol-induced excitation and that tolerance to this ethanol effect is modulated by Na + /K + ATPase function.T HE abuse of alcohol is a cause of significant societal and health-related problems. Despite the common usage of this drug, the molecular underpinnings of alcohol's acute actions on the brain are poorly understood. Alcohol (ethanol) has biphasic behavioral effects in humans and other animals, acting as a stimulant at lower concentrations and as a depressant at higher concentrations. Understanding the molecular nature of these biphasic effects is made difficult by the fact that ethanol interacts with, and alters the function of, many proteins, including neurotransmitter receptors and ion channels (Harris et al. 2008;Spanagel 2009). A commonly suggested class of ethanol targets is ligand-gated ion channels (LGICs), which include NMDA glutamate receptors, and members of a subclass of LGICs, the Cys-loop superfamily, including GABA A , glycine, and nicotinic acetylcholine receptors (nAChRs) (Olsen et al. 2014). Effects on the GABA A and glutamate receptors are hypothesized to play a significant role in the depressant effects of ethanol (Harris et al. 2008). Locomotor activation by low to moderate concentrations of ethanol in rodents is thought to model the euphoric effects of ethanol in humans (Phillips and Shen 1996). Locomotor activat...

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“…In rodent models, acute ethanol exposure leads to reduced vasopressin, oxytocin and growth hormone release with consequent perturbation in physiology and behavior (7), altered firing rates in nucleus accumbens (8) and dorsal root ganglia neurons (9), and alcohol-induced cerebral artery constriction (10,11). Moreover, studies in both mammals and invertebrate models demonstrate that ethanol targeting of neuronal BK is involved in development of alcohol tolerance and dependence (12)(13)(14)(15)(16). Although the physiological and behavioral consequences of ethanol disruption of BK function have been well documented, it remains unknown whether alcohol modification of BK function results from drug interaction with a defined recognition site(s) in a protein target vs. physical perturbation of the proteolipid environment where the BK protein resides.…”

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confidence: 99%

An alcohol-sensing site in the calcium- and voltage-gated, large conductance potassium (BK) channel

Bukiya

Kuntamallappanavar

Edwards

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Ethanol alters BK (slo1) channel function leading to perturbation of physiology and behavior. Site(s) and mechanism(s) of ethanol-BK channel interaction are unknown. We demonstrate that ethanol docks onto a water-accessible site that is strategically positioned between the slo1 calcium-sensors and gate. Ethanol only accesses this site in presence of calcium, the BK channel's physiological agonist. Within the site, ethanol hydrogen-bonds with K361. Moreover, substitutions that hamper hydrogen bond formation or prevent ethanol from accessing K361 abolish alcohol action without altering basal channel function. Alcohol interacting site dimensions are approximately 10.7 × 8.6 × 7.1 Å, accommodating effective (ethanol-heptanol) but not ineffective (octanol, nonanol) channel activators. This study presents: (i) to our knowledge, the first identification and characterization of an n-alkanol recognition site in a member of the voltage-gated TM6 channel superfamily; (ii) structural insights on ethanol allosteric interactions with ligand-gated ion channels; and (iii) a first step for designing agents that antagonize BK channel-mediated alcohol actions without perturbing basal channel function.is a psychoactive agent that has been overwhelmingly consumed by mankind across cultures and civilizations. Alcohol actions on central nervous system (CNS) physiology and behavior are largely independent of beverage type but due to ethanol itself (1). Ethanol alters cell excitability by modifying function of transmembrane (TM) ion channel proteins, including K + channels. These channels constitute the most heterogeneous and extensive group of ion channels, its members belonging to TM2, TM4, and TM6 protein superfamilies. Within this myriad of proteins, several K + channels have been shown to modify behavior in response to acute exposure to ethanol concentrations that reach the CNS and other excitable tissues during alcohol drinking (2-5). However, with the sole exception of the TM2, G protein-regulated inward rectifier K + (GIRK) channel (6), there is no structural information on ethanol-K + channel protein interacting sites currently available. Voltage/Ca 2+ -gated, large conductance K + channels (BK), which are members of the TM6 voltage-gated ion channel superfamily, constitute major mediators of alcohol actions in excitable tissues. Acute exposure to ethanol levels reached in CNS during alcohol intoxication alters BK-mediated currents and thus, elicits widespread and profound modifications in physiology and behavior. In rodent models, acute ethanol exposure leads to reduced vasopressin, oxytocin and growth hormone release with consequent perturbation in physiology and behavior (7), altered firing rates in nucleus accumbens (8) and dorsal root ganglia neurons (9), and alcohol-induced cerebral artery constriction (10, 11). Moreover, studies in both mammals and invertebrate models demonstrate that ethanol targeting of neuronal BK is involved in development of alcohol tolerance and dependence (12-16). Although the physiological and be...

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Lipid Environment Modulates the Development of Acute Tolerance to Ethanol in Caenorhabditis elegans

Cited by 39 publications

References 42 publications

SWI/SNF chromatin remodeling regulates alcohol response behaviors in Caenorhabditis elegans and is associated with alcohol dependence in humans

SWI/SNF chromatin remodeling regulates alcohol response behaviors in Caenorhabditis elegans and is associated with alcohol dependence in humans

A Novel Cholinergic Action of Alcohol and the Development of Tolerance to That Effect inCaenorhabditis elegans

An alcohol-sensing site in the calcium- and voltage-gated, large conductance potassium (BK) channel

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