The human gene KCNMA1 encodes a subunit of the primary BK ("big potassium") channel in human, a high-conductance calcium- and voltage-dependent potassium channel ("big" refers to the high conductance). BK channels are a known target of ethanol. There is a single orthologous gene in Drosophila, slo, for which classical loss-of-function and amorphic mutations, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. Dmel\slo is also orthologous to a second human gene, KCNU1.
A UAS construct of a tagged human Hsap\KCNMA1 gene has been introduced into flies, but has not been characterized in the context of this disease model.
Animals homozygous for amorphic alleles of Dmel\slo survive to adulthood; they exhibit multiple neurophysiology and behavioral defects, including circadian rhythm defects. In terms of response to alcohol, initial studies demonstrated that mutations in Dmel\slo affect development of tolerance; ethanol and benzyl alcohol were shown to be affected similarly and to produce mutual cross-tolerance. Dmel\slo mutations have been used to characterize the relationship between tolerance and withdrawal; withdrawal seizures are observed in this Drosophila system. (Note that human KCNMA1 is implicated in two diseases associated with seizures; see MIM:609446 and MIM:617643.) Physical and genetic interactions have been described for Dmel\slo; see below and in the slo gene report.
[updated Feb. 2019 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]
Mammalian BK channels are a known target of ethanol, with different effects and different mechanisms observed for acute vs. protracted exposure (reviewed in Dopico et al., 2014; pubmed:25538625).
The large-conductance voltage- and Ca(2+)-activated K+ channel, also called the BK channel, differs from other K+ channels in that it can be activated by both intracellular Ca(2+) ions and by membrane depolarization. The BK channel consists of 4 alpha subunits and 4 optional auxiliary beta subunits. The pore-forming alpha subunit is encoded by the KCNMA1 gene, which produces multiple isoforms through alternative splicing. The 4 beta subunits are encoded by different genes that show tissue-specific expression (Sausbier et al., 2004; pubmed:15194823). [from MIM:600150; 2017.12.20]
Many to one: 2 human to 1 Drosophila; the second human gene is KCNU1.
High-scoring ortholog of human KCNMA1; moderate-scoring ortholog of KCNU1 (1 Drosophila to 2 human). Dmel\slo shares 52% identity and 64% similarity with KCNMA1.
