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FB2026_01
,
released March 12, 2026
Several studies in Drosophila have implicated genes encoding proteins belonging to the K2P (two pore) voltage-gated potassium channel superfamily in the development of cardiac arrhythmia. The Drosophila genes Ork1 (most closely related to the human gene KCNK4), sand and galene (both closely related to the human gene KCNK18) have been identified and characterized in the context of cardiac dysfunction. In human, KCNK18 has been implicated in susceptibility to migraine.
A UAS construct of a wild-type human Hsap\KCNK4 gene has been introduced into flies, but has not been characterized. None of the other human KCNK genes has been introduced into flies.
In the case of Dmel\Ork1, cardiac-specific inactivation leads to an increase in heart rhythm (as assayed in larvae); overexpression in the whole cardiac tube during larval stages results in a complete arrest of heart beating and a totally dilated cardiac tube. Ork1 activity appears to set the cardiac rhythm by controlling the duration of the slow diastolic depolarization phase. ORK1-overexpressing cardiomyocytes remain excitable and have not been affected in their contractility. RNAi-targeting constructs and alleles caused by insertional mutagenesis have been generated for Dmel\Ork1; a small number of genetic and physical interactions have been reported.
Dmel\sand and Dmel\galene have been found to play a role in age-dependent diastolic heart failure. In Drosophila, as in humans, reduced heart function associated with normal aging manifests primarily as defects in relaxation (diastole) while preserving contractile performance. Loss-of-function mutations in these two genes exhibit only minor cardiac defects early in life. However, progressive defects in transitioning from systole to diastole become apparent in aged animals; their hearts are described as constitutively contracting. Investigated in more detail, the cardiac phenotype of loss-of-function mutations of sand appears likely to reflect a loss of repolarization, rather than structurally congestive remodeling. It is postulated that sand and galene encode two subunits that form a heteromeric ion channel. RNAi-targeting constructs have been generated for both sand and galene; for sand, an allele caused by insertional mutagenesis and a small deletion encompassing the gene have also been generated.
[updated Oct. 2019 by FlyBase; FBrf0222196]
The term "arrhythmia" refers to any change from the normal sequence of electrical impulses in the heart, such as atrial fibrillation, bradycardia (slow heartbeat), tachycardia (rapid heart rate), conduction disorders, rhythm disorders, ventricular fibrillation, premature contractions. Arrhythmias may be completely harmless or life-threatening. (http://www.heart.org/HEARTORG/Conditions/Arrhythmia/AboutArrhythmia/About-Arrhythmia_UCM_002010_Article.jsp)
KCNK18 and KCNK4 encode members of the K2P superfamily of potassium channel proteins containing two pore-forming P domains; the encoded proteins function as outward rectifying potassium channels. May function as background potassium channel that sets the resting membrane potential. [Gene Cards, KCNK18; 2018.05.21]
See HGNC "Gene Family: Potassium two pore domain channel subfamily K (KCNK)" (https://www.genenames.org/cgi-bin/genefamilies/set/277). There are 15 members of this gene family identified in human; there are 10 identified in Drosophila.
TRAAK channels such as KCNK4, members of the 2 pore domain potassium ion channel family K2P, are expressed almost exclusively in the nervous system and control the resting membrane potential. [from MIM:605720; 2018.05.24]
Two-pore domain (K2P) potassium channels, such as KCNK18, give rise to background, or leak, potassium conductance, and they regulate diverse cellular functions by adjusting both the resting membrane potential and excitability. KCNK18 (originally TRESK) is unique among this family of potassium channels in that its activity is regulated by intracellular calcium (summary by Czirjak and Enyedi, 2006; pubmed:16569637). [from MIM:613655; 2018.05.24]
Many to one (many human to 1 Drosophila); additional lower-scoring orthologs in both species.
One to many (1 human to many Drosophila); additional lower-scoring orthologs in both species.
Moderate-scoring ortholog of human KCNK18; many related genes in both species. Dmel\sand is most closely related to KCNK18 (reciprocal best hit); it shares 21% identity and 40% similarity with this human gene.
Moderate-scoring ortholog of human KCNK18; many related genes in both species. Dmel\CG9194 is most closely related to KCNK18; it shares 17% identity and 27% similarity with this human gene.
Moderate-scoring ortholog of human KCNK4; many related genes in both species. Dmel\Ork1 is most closely related to KCNK4 (reciprocal best hit); it shares 27% identity and 44% similarity with this human gene.