Academic journal article Genetics

Small Heat Shock Proteins Are Novel Common Determinants of Alcohol and Nicotine Sensitivity in Caenorhabditis Elegans

Academic journal article Genetics

Small Heat Shock Proteins Are Novel Common Determinants of Alcohol and Nicotine Sensitivity in Caenorhabditis Elegans

Article excerpt

THE most commonly used pharmacological addictive substances are alcohol and nicotine and the economic burden from abuse of these substances is extremely high. Indeed, tobacco and alcohol use account for 6 million and 2.5million deaths per year, respectively (World Health Organization 2010, 2011). Although environmental factors play a role in addiction, heritability estimates for nicotine and alcohol range between 30 and 60%(Bierut 2011; Agrawal et al. 2012;Wang et al. 2012; Demers et al. 2014; Buhler et al. 2015). One factor thought to play a role in the acquisition of substance dependence is an individual's initial level of response to the drug, which is itself genetically influenced (Schuckit et al. 2004; Schuckit et al. 2011, 2012). Nicotine acts physiologically as a nervous system stimulant through direct binding and activation of nicotinic acetylcholine receptors (Dani and Balfour 2011). Additional factors that influence nicotine sensitivity have been identified, such as transient receptor potential (TRP) channels (Feng et al. 2006; Talavera et al. 2009). In contrast to nicotine, alcohol is a nervous system depressant thought to function by low-affinity interactions with specific target proteins (Howard et al. 2011; Trudell et al. 2014), such as protein kinase C (Newton and Ron 2007; Das et al. 2009), ormembrane receptors and ion channels, for example GABAA receptors (Aryal et al. 2009; Bodhinathan and Slesinger 2013; Howard et al. 2014). Although many modulators of alcohol sensitivity have been identified (Davies et al. 2003; Kapfhamer et al. 2008; Pietrzykowski et al. 2008; Barclay et al. 2010; Kaun et al. 2012), our understanding of acute alcohol action within the nervous system remains incomplete.

Genome-wide association studies (GWAS) on nicotine and alcohol dependence behaviors have identified potential contributing factors (Bierut 2011; Agrawal et al. 2012; Wang et al. 2012; Demers et al. 2014; Buhler et al. 2015) often reinforcing the link between modulators of substance efficacy or sensitivity and addictive predisposition. For alcohol, contributing factors reliably identified are enzymes involved in its metabolism, such as alcohol and aldehyde dehydrogenases (Edenberg et al. 2006; Frank et al. 2012; Gelernter et al. 2014; Quillen et al. 2014) as well as direct pharmacological targets such as GABAA receptors (Bierut et al. 2010). For nicotine dependence, GWAS studies have also identified metabolic enzymes (Thorgeirsson et al. 2008) as well as the endogenous pharmacological target for nicotine, the nicotinic acetylcholine receptors (Bierut et al. 2007; Liu et al. 2010; Kapoor et al. 2012). Despite explicit pharmacological differences between addictive substances, such as alcohol and nicotine, data from family and twin analyses support the contribution of unidentified common genetic factors underlying substance dependence (Funk et al. 2006; Bierut 2011; Agrawal et al. 2012). Identification of these common factors, therefore, is a key unresolved question in addiction research and of considerable clinical and therapeutic importance.

Exposure of cells, tissues, or organisms to a stressful or harmful environment can activate the heat shock response, an upregulation in the expression of members of the heat shock protein (HSP) family of cellular chaperones. Indeed acute exposure to stressful concentrations of ethanol in Caenorhabditis elegans increases expression of a small number of genes, in particular a subset of HSPs (Kwon et al. 2004) and acute alcohol addition to cultured mouse neurons also induces HSP expression (Pignataro et al. 2007). Control over HSP expression, under both basal and stressful conditions, is governed by the heat shock transcription factor (HSF) (Anckar and Sistonen 2011). Here we characterize that HSF-1 is a codeterminant of both alcohol and nicotine sensitivity in C. elegans and that this phenotype requires the small HSP, HSP-16.48, a homolog of human a-crystallin.We showfurther that HSP-16. …

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