Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHI2N71)

• DOT Name: Potassium voltage-gated channel subfamily A member 5 (KCNA5)
• Synonyms: HPCN1; Voltage-gated potassium channel HK2; Voltage-gated potassium channel subunit Kv1.5
• Gene Name: KCNA5
• Related Disease:
  Atrial fibrillation, familial, 7
  Familial atrial fibrillation
• UniProt ID: KCNA5_HUMAN
• Pfam ID: PF02214 ; PF00520
• Sequence:
  MEIALVPLENGGAMTVRGGDEARAGCGQATGGELQCPPTAGLSDGPKEPAPKGRGAQRDA
  DSGVRPLPPLPDPGVRPLPPLPEELPRPRRPPPEDEEEEGDPGLGTVEDQALGTASLHHQ
  RVHINISGLRFETQLGTLAQFPNTLLGDPAKRLRYFDPLRNEYFFDRNRPSFDGILYYYQ
  SGGRLRRPVNVSLDVFADEIRFYQLGDEAMERFREDEGFIKEEEKPLPRNEFQRQVWLIF
  EYPESSGSARAIAIVSVLVILISIITFCLETLPEFRDERELLRHPPAPHQPPAPAPGANG
  SGVMAPPSGPTVAPLLPRTLADPFFIVETTCVIWFTFELLVRFFACPSKAGFSRNIMNII
  DVVAIFPYFITLGTELAEQQPGGGGGGQNGQQAMSLAILRVIRLVRVFRIFKLSRHSKGL
  QILGKTLQASMRELGLLIFFLFIGVILFSSAVYFAEADNQGTHFSSIPDAFWWAVVTMTT
  VGYGDMRPITVGGKIVGSLCAIAGVLTIALPVPVIVSNFNYFYHRETDHEEPAVLKEEQG
  TQSQGPGLDRGVQRKVSGSRGSFCKAGGTLENADSARRGSCPLEKCNVKAKSNVDLRRSL
  YALCLDTSRETDL
• Function: Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes. Forms tetrameric potassium-selective channels through which potassium ions pass in accordance with their electrochemical gradient. The channel alternates between opened and closed conformations in response to the voltage difference across the membrane. Can form functional homotetrameric channels and heterotetrameric channels that contain variable proportions of KCNA1, KCNA2, KCNA4, KCNA5, and possibly other family members as well; channel properties depend on the type of alpha subunits that are part of the channel. Channel properties are modulated by cytoplasmic beta subunits that regulate the subcellular location of the alpha subunits and promote rapid inactivation. Homotetrameric channels display rapid activation and slow inactivation. May play a role in regulating the secretion of insulin in normal pancreatic islets. Isoform 2 exhibits a voltage-dependent recovery from inactivation and an excessive cumulative inactivation.
• Tissue Specificity: Pancreatic islets and insulinoma.
• Reactome Pathway:
  Phase 3 - rapid repolarisation (R-HSA-5576890)
  Voltage gated Potassium channels (R-HSA-1296072)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Atrial fibrillation, familial, 7	DISL1TMA	Strong	Autosomal dominant	[1]
Familial atrial fibrillation	DISL4AGF	Supportive	Autosomal dominant	[2]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Potassium voltage-gated channel subfamily A member 5 (KCNA5) increases the response to substance of Doxorubicin.	[16]
Cisplatin	DMRHGI9	Approved	Potassium voltage-gated channel subfamily A member 5 (KCNA5) increases the response to substance of Cisplatin.	[16]
Fluorouracil	DMUM7HZ	Approved	Potassium voltage-gated channel subfamily A member 5 (KCNA5) increases the response to substance of Fluorouracil.	[16]

13 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Potassium voltage-gated channel subfamily A member 5 (KCNA5).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Potassium voltage-gated channel subfamily A member 5 (KCNA5).	[4]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Potassium voltage-gated channel subfamily A member 5 (KCNA5).	[3]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Potassium voltage-gated channel subfamily A member 5 (KCNA5).	[5]
Progesterone	DMUY35B	Approved	Progesterone decreases the activity of Potassium voltage-gated channel subfamily A member 5 (KCNA5).	[6]
Bepridil	DM0RKS4	Approved	Bepridil decreases the activity of Potassium voltage-gated channel subfamily A member 5 (KCNA5).	[7]
Pergolide mesylate	DM5GKOV	Approved	Pergolide mesylate decreases the activity of Potassium voltage-gated channel subfamily A member 5 (KCNA5).	[8]
Ebastine	DMH21D9	Phase 4	Ebastine decreases the activity of Potassium voltage-gated channel subfamily A member 5 (KCNA5).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Potassium voltage-gated channel subfamily A member 5 (KCNA5).	[11]
Eugenol	DM7US1H	Patented	Eugenol decreases the activity of Potassium voltage-gated channel subfamily A member 5 (KCNA5).	[12]
Terfenadine	DM4KLPT	Withdrawn from market	Terfenadine decreases the activity of Potassium voltage-gated channel subfamily A member 5 (KCNA5).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Potassium voltage-gated channel subfamily A member 5 (KCNA5).	[14]
acrolein	DMAMCSR	Investigative	acrolein increases the expression of Potassium voltage-gated channel subfamily A member 5 (KCNA5).	[15]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Potassium voltage-gated channel subfamily A member 5 (KCNA5).	[10]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] Novel KCNA5 loss-of-function mutations responsible for atrial fibrillation. J Hum Genet. 2009 May;54(5):277-83. doi: 10.1038/jhg.2009.26. Epub 2009 Apr 3.
• [3] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [4] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [5] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [6] Differential effects of estrogen and progesterone on potassium channels expressed in Xenopus oocytes. Steroids. 2008 Mar;73(3):272-9. doi: 10.1016/j.steroids.2007.10.010. Epub 2007 Nov 4.
• [7] Inhibitory effect of bepridil on hKv1.5 channel current: comparison with amiodarone and E-4031. Eur J Pharmacol. 2001 Nov 2;430(2-3):149-57. doi: 10.1016/s0014-2999(01)01381-4.
• [8] Pergolide is an inhibitor of voltage-gated potassium channels, including Kv1.5, and causes pulmonary vasoconstriction. Circulation. 2005 Sep 6;112(10):1494-9. doi: 10.1161/CIRCULATIONAHA.105.556704. Epub 2005 Aug 29.
• [9] Comparative effects of nonsedating histamine H1 receptor antagonists, ebastine and terfenadine, on human Kv1.5 channels. Eur J Pharmacol. 1997 May 20;326(2-3):257-63. doi: 10.1016/s0014-2999(97)85421-0.
• [10] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [11] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [12] Eugenol inhibits K+ currents in trigeminal ganglion neurons. J Dent Res. 2007 Sep;86(9):898-902. doi: 10.1177/154405910708600918.
• [13] HERG, a primary human ventricular target of the nonsedating antihistamine terfenadine. Circulation. 1996 Aug 15;94(4):817-23. doi: 10.1161/01.cir.94.4.817.
• [14] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [15] Mitochondrial ROS-K+ channel signaling pathway regulated secretion of human pulmonary artery endothelial cells. Free Radic Res. 2012 Dec;46(12):1437-45. doi: 10.3109/10715762.2012.724532. Epub 2012 Sep 27.
• [16] Detection of potassium currents and regulation of multidrug resistance by potassium channels in human gastric cancer cells. Cell Biol Int. 2007 Jul;31(7):741-7. doi: 10.1016/j.cellbi.2007.01.008. Epub 2007 Jan 21.