This report describes characterization of the fly alcohol response using the Drosophila gene InR, the fly ortholog of human insulin receptor INSR. In flies, Dmel\InR is one of several genes of the insulin signaling pathway implicated in responses to ethanol (see FBhh0000692). Classical hypomorphic alleles, a constitutively active dominant-negative allele, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for Dmel\InR. Dmel\InR is also orthologous to human genes IGF1R and INSRR.
A UAS construct carrying the human Hsap\INSR gene has been introduced into flies, but has not been used to investigate responses to alcohol.
Loss-of-function alleles of Dmel\InR are lethal. Some compound heterozygous combinations survive to adulthood; they exhibit reduced body weight relative to controls; lipid and carbohydrate content are increased relative to controls. Pan-neuronal expression of a constitutively active mutation of InR results in reduced sensitivity to ethanol-induced sedation. Many physical interactions and genetic interactions of Dmel\InR have been described; see below and in the gene report for InR.
[updated Jan. 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).
Alcoholism is a multifactorial, genetically influenced disorder. [from MIM:103780; 2017.12.19]
INSR is a receptor tyrosine kinase which mediates the pleiotropic actions of insulin. [from UniProt:P06213; 2018.01.10]
After removal of the precursor signal peptide, the insulin receptor precursor is post-translationally cleaved into two chains (alpha and beta) that are covalently linked. Binding of insulin or other ligands to this receptor activates the insulin signaling pathway, which regulates glucose uptake and release, as well as the synthesis and storage of carbohydrates, lipids and protein. [from Gene Cards, INSR; 2018.01.10]
Insulin receptor is a tetramer of 2 alpha and 2 beta subunits; the alpha and beta subunits are coded by a single gene and are joined by disulfide bonds, a mechanism parallel to that of its ligand, insulin (INS). [from MIM:147670; 2018.01.10]
Many to one: 3 human to 1 Drosophila; additional orthologous genes in human are IGF1R and INSRR.
Ortholog of human genes INSR, IGF1R and INSRR (1 Drosophila to 3 human). Dmel\InR shares 36-37% identity and 51-54% similarity with the human genes.
