This report describes characterization of the fly response to alcohol using Drosophila genes that encode an NMDA receptor or products that interact with an NMDA receptor. Perturbations of expression of fly genes dlg1 (orthologous to human DLG1, DLG2, DLG3, and DLG4, multi-domain membrane-associated scaffolding proteins of the MAGUK superfamily), Nmdar1 (ortholog of human GRIN1, which encodes a subunit of the NMDAR glutamate receptor and ion channel protein), and CASK (ortholog of human CASK, a calcium/calmodulin-dependent kinase that is also a multi-domain membrane-associated scaffolding proteins of the MAGUK superfamily) result in changes in development of tolerance to ethanol and in sensitivity to ethanol sedation.
Several of the human genes enumerated above are implicated in forms of intellectual disability or syndromes that include intellectual disability (MIM:300850, MIM:614254, MIM:300749). Hsap\CASK has been introduced into flies; heterologous rescue (functional complementation) is observed: expression of a transgenic copy of Hsap\CASK in specific neurons of the adult brain rescues the memory and learning phenotypes exhibited by loss-of-function mutations of Dmel\CASK. Hsap\DLG4 has been introduced into flies, but has not been characterized further. The human GRIN1 gene has not been introduced into flies.
In a genetic screen for mutants exhibiting altered response to repeated ethanol exposure, an insertion allele of the fly gene dlg1 exhibited severely reduced tolerance development and a small but statistically significant decrease in ethanol sensitivity. The mutation was determined to affect only the long isoforms of dlg1. Since the human ortholog DLG1 is known to interact with human NMDA receptors, mutations of one of the Drosophila NMDA receptor genes, Nmdar1, were characterized. Loss-of-function mutations of Dmel\Nmdar1 result in reduced development of both rapid and chronic tolerance to ethanol. The human DLG1 protein is also known to interact with human CASK; hypomorphic mutations of Dmel\CASK exhibit severely reduced tolerance and increased sensitivity to ethanol sedation.
Loss-of-function mutations of Dmel\Nmdar1 and Dmel\CASK result in multiple behavioral and neuroanatomy defects, including defects in memory and learning. Loss-of-function mutations of Dmel\dlg1 are lethal, usually at the larval or pupal stage; in larvae, neuroanatomy and neurophysiology phenotypes, as well as tumorigenic phenotypes, are frequently observed. Physical and genetic interactions for all three genes have been described; see below and in the relevant gene reports.
[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]
Human DLG1 encodes an essential multidomain membrane-associated scaffolding protein required for normal development. The encoded protein is a member of the MAGUK protein family. It recruits channels, receptors and signaling molecules to discrete plasma membrane domains in polarized cells and may play a role in adherens junction assembly, signal transduction, cell proliferation, synaptogenesis and lymphocyte activation. [Gene Cards, DLG1; 2018.01.17]
GRIN1 encodes a subunit of the NMDAR glutamate receptor and ion channel protein; it plays a key role in the plasticity of synapses, which is believed to underlie memory and learning. [Gene Cards, GRIN1; 2018.01.17]
The CASK gene encodes a calcium/calmodulin-dependent serine protein kinase. The encoded protein is a member of the MAGUK protein family, multidomain membrane-associated scaffolding proteins with roles in synaptic transmembrane protein anchoring and ion channel trafficking. [Gene Cards, CASK; 2018.01.17]
Many to one (2 human to 1 Drosophila). An additional human gene, MPP1, is a low-scoring ortholog of Dmel\CASK
Many to one (4 human to 1 Drosophila); the other human genes are DLG4, DLG2, and DLG3.
One to one (1 human to 1 Drosophila).
Moderate- to high-scoring ortholog of human DLG1, DLG4, DLG2, and DLG3 (1 Drosophila to 4 human). Dmel\dlg1 shares 40-49% identity and 55-63% similarity with the human genes.
High-scoring ortholog of human GRIN1 (1 Drosophila to 1 human). Dmel\Nmdar1 shares 46% identity and 65% similarity with the human gene.
High-scoring ortholog of human CASK; low-scoring otholog of human MPP1 (1 Drosophila to 2 human). Dmel\CASK shares 60% identity and 75% similarity with the human CASK gene.
