Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIFUVV7)

• DOT Name: Potassium voltage-gated channel subfamily D member 2 (KCND2)
• Synonyms: Voltage-gated potassium channel subunit Kv4.2
• Gene Name: KCND2
• Related Disease:
  Cardiac arrest
  Cerebral infarction
  Hepatocellular carcinoma
  Gastric cancer
  Stomach cancer
  Arrhythmia
  Autism
  Brugada syndrome
  Complex neurodevelopmental disorder
  Epilepsy
  Long QT syndrome
  Temporal lobe epilepsy
• UniProt ID: KCND2_HUMAN
• PDB ID: 7E7Z; 7E83; 7E84; 7E87; 7E8B; 7E8E; 7E8H; 7F0J; 7F3F; 7UK5; 7UKC; 7UKD; 7UKE; 7UKF; 7UKG; 7UKH
• Pfam ID: PF02214 ; PF11879 ; PF00520 ; PF11601
• Sequence:
  MAAGVAAWLPFARAAAIGWMPVASGPMPAPPRQERKRTQDALIVLNVSGTRFQTWQDTLE
  RYPDTLLGSSERDFFYHPETQQYFFDRDPDIFRHILNFYRTGKLHYPRHECISAYDEELA
  FFGLIPEIIGDCCYEEYKDRRRENAERLQDDADTDTAGESALPTMTARQRVWRAFENPHT
  STMALVFYYVTGFFIAVSVIANVVETVPCGSSPGHIKELPCGERYAVAFFCLDTACVMIF
  TVEYLLRLAAAPSRYRFVRSVMSIIDVVAILPYYIGLVMTDNEDVSGAFVTLRVFRVFRI
  FKFSRHSQGLRILGYTLKSCASELGFLLFSLTMAIIIFATVMFYAEKGSSASKFTSIPAA
  FWYTIVTMTTLGYGDMVPKTIAGKIFGSICSLSGVLVIALPVPVIVSNFSRIYHQNQRAD
  KRRAQKKARLARIRAAKSGSANAYMQSKRNGLLSNQLQSSEDEQAFVSKSGSSFETQHHH
  LLHCLEKTTNHEFVDEQVFEESCMEVATVNRPSSHSPSLSSQQGVTSTCCSRRHKKTFRI
  PNANVSGSHQGSIQELSTIQIRCVERTPLSNSRSSLNAKMEECVKLNCEQPYVTTAIISI
  PTPPVTTPEGDDRPESPEYSGGNIVRVSAL
• Function: Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes, primarily in the brain. Mediates the major part of the dendritic A-type current I(SA) in brain neurons. This current is activated at membrane potentials that are below the threshold for action potentials. It regulates neuronal excitability, prolongs the latency before the first spike in a series of action potentials, regulates the frequency of repetitive action potential firing, shortens the duration of action potentials and regulates the back-propagation of action potentials from the neuronal cell body to the dendrites. Contributes to the regulation of the circadian rhythm of action potential firing in suprachiasmatic nucleus neurons, which regulates the circadian rhythm of locomotor activity. Functions downstream of the metabotropic glutamate receptor GRM5 and plays a role in neuronal excitability and in nociception mediated by activation of GRM5. Mediates the transient outward current I(to) in rodent heart left ventricle apex cells, but not in human heart, where this current is mediated by another family member. 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 KCND2 and KCND3; channel properties depend on the type of pore-forming alpha subunits that are part of the channel. In vivo, membranes probably contain a mixture of heteromeric potassium channel complexes. Interaction with specific isoforms of the regulatory subunits KCNIP1, KCNIP2, KCNIP3 or KCNIP4 strongly increases expression at the cell surface and thereby increases channel activity; it modulates the kinetics of channel activation and inactivation, shifts the threshold for channel activation to more negative voltage values, shifts the threshold for inactivation to less negative voltages and accelerates recovery after inactivation. Likewise, interaction with DPP6 or DPP10 promotes expression at the cell membrane and regulates both channel characteristics and activity.
• Tissue Specificity: Detected in ovary, in corpus luteum and in granulosa and theca cells in the follicle (at protein level) . Highly expressed throughout the brain . Detected in amygdala, caudate nucleus, cerebellum, hippocampus, substantia nigra and thalamus . Expression is not detectable or very low in heart, kidney, liver, lung, pancreas and skeletal muscle . Not detectable in human heart atrium .
• KEGG Pathway: Serotonergic sy.pse (hsa04726)
• Reactome Pathway:
  Phase 1 - inactivation of fast Na+ channels (R-HSA-5576894)
  Voltage gated Potassium channels (R-HSA-1296072)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiac arrest	DIS9DIA4	Strong	Genetic Variation	[1]
Cerebral infarction	DISR1WNP	Strong	Biomarker	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[3]
Gastric cancer	DISXGOUK	moderate	Altered Expression	[4]
Stomach cancer	DISKIJSX	moderate	Altered Expression	[4]
Arrhythmia	DISFF2NI	Limited	Genetic Variation	[5]
Autism	DISV4V1Z	Limited	Biomarker	[6]
Brugada syndrome	DISSGN0E	Limited	Biomarker	[5]
Complex neurodevelopmental disorder	DISB9AFI	Limited	Autosomal dominant	[7]
Epilepsy	DISBB28L	Limited	Biomarker	[6]
Long QT syndrome	DISMKWS3	Limited	Genetic Variation	[8]
Temporal lobe epilepsy	DISNOPXX	Limited	Biomarker	[9]

This DOT Affected the Regulation of Drug Effects of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Adenosine triphosphate	DM79F6G	Approved	Potassium voltage-gated channel subfamily D member 2 (KCND2) increases the abundance of Adenosine triphosphate.	[20]
Milchsaure	DM462BT	Investigative	Potassium voltage-gated channel subfamily D member 2 (KCND2) increases the secretion of Milchsaure.	[20]
D-glucose	DMMG2TO	Investigative	Potassium voltage-gated channel subfamily D member 2 (KCND2) increases the import of D-glucose.	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Potassium voltage-gated channel subfamily D member 2 (KCND2).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Potassium voltage-gated channel subfamily D member 2 (KCND2).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Potassium voltage-gated channel subfamily D member 2 (KCND2).	[11]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Potassium voltage-gated channel subfamily D member 2 (KCND2).	[12]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Potassium voltage-gated channel subfamily D member 2 (KCND2).	[13]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Potassium voltage-gated channel subfamily D member 2 (KCND2).	[12]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Potassium voltage-gated channel subfamily D member 2 (KCND2).	[11]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Potassium voltage-gated channel subfamily D member 2 (KCND2).	[14]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Potassium voltage-gated channel subfamily D member 2 (KCND2).	[15]
Acocantherin	DM7JT24	Approved	Acocantherin increases the expression of Potassium voltage-gated channel subfamily D member 2 (KCND2).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Potassium voltage-gated channel subfamily D member 2 (KCND2).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Potassium voltage-gated channel subfamily D member 2 (KCND2).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Potassium voltage-gated channel subfamily D member 2 (KCND2).	[19]

References

• [1] Evaluation of genes encoding for the transient outward current (Ito) identifies the KCND2 gene as a cause of J-wave syndrome associated with sudden cardiac death.Circ Cardiovasc Genet. 2014 Dec;7(6):782-9. doi: 10.1161/CIRCGENETICS.114.000623. Epub 2014 Sep 11.
• [2] Post-treatment with a Hydrogen Sulfide Donor Limits Neuronal Injury and Modulates Potassium Voltage-gated Channel Subfamily D Member 2 (Kv4.2) and Potassium Channel Interacting Protein 3 (KChIP3) During Transient Global Cerebral Ischemia.Curr Neurovasc Res. 2017;14(4):397-405. doi: 10.2174/1567202614666171108113447.
• [3] Six genes as potential diagnosis and prognosis biomarkers for hepatocellular carcinoma through data mining.J Cell Physiol. 2019 Jun;234(6):9787-9792. doi: 10.1002/jcp.27664. Epub 2018 Dec 17.
• [4] KCND2 upregulation might be an independent indicator of poor survival in gastric cancer.Future Oncol. 2018 Nov;14(27):2811-2820. doi: 10.2217/fon-2018-0418. Epub 2018 Jul 27.
• [5] Genomic organisation and chromosomal localisation of two members of the KCND ion channel family, KCND2 and KCND3.Hum Genet. 2000 Jun;106(6):614-9. doi: 10.1007/s004390000308.
• [6] Kv4.2 autism and epilepsy mutation enhances inactivation of closed channels but impairs access to inactivated state after opening.Proc Natl Acad Sci U S A. 2018 Apr 10;115(15):E3559-E3568. doi: 10.1073/pnas.1717082115. Epub 2018 Mar 26.
• [7] Exome sequencing identifies de novo gain of function missense mutation in KCND2 in identical twins with autism and seizures that slows potassium channel inactivation. Hum Mol Genet. 2014 Jul 1;23(13):3481-9. doi: 10.1093/hmg/ddu056. Epub 2014 Feb 5.
• [8] Mutations in the genes KCND2 and KCND3 encoding the ion channels Kv4.2 and Kv4.3, conducting the cardiac fast transient outward current (ITO,f), are not a frequent cause of long QT syndrome.Clin Chim Acta. 2005 Jan;351(1-2):95-100. doi: 10.1016/j.cccn.2004.08.017.
• [9] A Kv4.2 truncation mutation in a patient with temporal lobe epilepsy.Neurobiol Dis. 2006 Nov;24(2):245-53. doi: 10.1016/j.nbd.2006.07.001. Epub 2006 Aug 24.
• [10] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [11] 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.
• [12] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [13] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [14] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [15] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [16] Ouabain at pathological concentrations might induce damage in human vascular endothelial cells. Acta Pharmacol Sin. 2006 Feb;27(2):165-72. doi: 10.1111/j.1745-7254.2006.00244.x.
• [17] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [18] 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.
• [19] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.
• [20] Long noncoding RNA FAM66C promotes tumor progression and glycolysis in intrahepatic cholangiocarcinoma by regulating hsa-miR-23b-3p/KCND2 axis. Environ Toxicol. 2021 Nov;36(11):2322-2332. doi: 10.1002/tox.23346. Epub 2021 Aug 21.