This report describes characterization of the fly alcohol response using Drosophila genes within the EGFR and MAPK/ERK signaling pathways. Multiple cell surface receptors have been shown to activate the MAPK/ERK signaling pathway (also called the RAS-RAF-MEK-ERK pathway), including EGFR. Mutations in fly genes Egfr, rl (orthologous to multiple human MAPK genes), spi (an EGFR ligand), rho (an activator of spi), and S (a regulator of cellular trafficking of EGFR ligands) all exhibit changes in ethanol sensitivity.
In a genetic screen for mutants with altered sensitivity to ethanol sedation, alleles of the Drosophila MAP4K mitogen-activated protein kinase hppy exhibited a decrease in ethanol sensitivity (resistance to ethanol-induced sedation); see FBhh0000684. Since MAPKs are known to act via the JNK, p38, and MAPK/ERK signaling pathways, additional mutations in Drosophila genes within these pathways were assessed for ethanol sensitivity. Only genes within the MAPK/ERK pathway and the upstream EGFR signaling pathway exhibited changes in sensitivity: activated or overexpressing mutations result in decreased sensitivity; loss-of-function alleles result in increased sensitivity. See also the human disease model report alcohol, response to, EPS8-related (FBhh0000688).
Administration of EGFR inhibitors [erlotinib (Tarceva) or gefitinib (Iressa)] to adult animals by feeding also results in increased ethanol sensitivity. Thus, in flies, inhibition of the EGFR pathway during adulthood is sufficient to produce enhanced ethanol sensitivity.
[updated Dec. 2018 by FlyBase; FBrf0222196]
Alcoholism can be defined as persistence of excessive drinking over a long period of time despite adverse health effects and disruption of social relations (Morozova et al., 2014; pubmed:24395673).
The 2013 Diagnostic and Statistical Manual of Mental Disorders (DSM) combined the two former categorizations of abnormal alcohol use (alcohol abuse and alcohol dependence) into one diagnosis: alcohol use disorder. The severity of an individual's AUD is broken into classifications: mild, moderate, or severe. "Alcoholism" is a non-medical term often used to describe a severe form of alcohol use disorder. (https://www.therecoveryvillage.com/recovery-blog/alcoholism-alcohol-use-disorder-whats-difference/)
Excessive alcohol consumption is associated with increased risk of different types of cancer, higher cardiovascular disease mortality, birth defects, liver diseases, and neuropsychiatric disorders (Morozova et al., 2014; pubmed:24395673).
Epidermal Growth Factor Receptor (EGFR) is a transmembrane receptor tyrosine kinase of the ErbB family. Binding of the protein to a ligand induces receptor dimerization and tyrosine autophosphorylation and leads to cell proliferation. Binding of EGFR can activate at least 4 major downstream signaling cascades including the RAS-RAF-MEK-ERK, PI3 kinase-AKT, PLCgamma-PKC and STATs modules. [from Gene Cards, EGFR; 2016.09.30]