Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRPIH7J)

• DOT Name: Potassium voltage-gated channel subfamily D member 3 (KCND3)
• Synonyms: Voltage-gated potassium channel subunit Kv4.3
• Gene Name: KCND3
• Related Disease:
  Spinocerebellar ataxia type 19/22
  Brugada syndrome 1
  Brugada syndrome 9
• UniProt ID: KCND3_HUMAN
• PDB ID: 1S1G; 2NZ0; 7W3Y; 7W6N; 7W6S; 7W6T
• Pfam ID: PF02214 ; PF11879 ; PF00520 ; PF11601
• Sequence:
  MAAGVAAWLPFARAAAIGWMPVANCPMPLAPADKNKRQDELIVLNVSGRRFQTWRTTLER
  YPDTLLGSTEKEFFFNEDTKEYFFDRDPEVFRCVLNFYRTGKLHYPRYECISAYDDELAF
  YGILPEIIGDCCYEEYKDRKRENAERLMDDNDSENNQESMPSLSFRQTMWRAFENPHTST
  LALVFYYVTGFFIAVSVITNVVETVPCGTVPGSKELPCGERYSVAFFCLDTACVMIFTVE
  YLLRLFAAPSRYRFIRSVMSIIDVVAIMPYYIGLVMTNNEDVSGAFVTLRVFRVFRIFKF
  SRHSQGLRILGYTLKSCASELGFLLFSLTMAIIIFATVMFYAEKGSSASKFTSIPASFWY
  TIVTMTTLGYGDMVPKTIAGKIFGSICSLSGVLVIALPVPVIVSNFSRIYHQNQRADKRR
  AQKKARLARIRVAKTGSSNAYLHSKRNGLLNEALELTGTPEEEHMGKTTSLIESQHHHLL
  HCLEKTTGLSYLVDDPLLSVRTSTIKNHEFIDEQMFEQNCMESSMQNYPSTRSPSLSSHP
  GLTTTCCSRRSKKTTHLPNSNLPATRLRSMQELSTIHIQGSEQPSLTTSRSSLNLKADDG
  LRPNCKTSQITTAIISIPTPPALTPEGESRPPPASPGPNTNIPSIASNVVKVSAL
• Function: Pore-forming (alpha) subunit of voltage-gated rapidly inactivating A-type potassium channels. May contribute to I(To) current in heart and I(Sa) current in neurons. Channel properties are modulated by interactions with other alpha subunits and with regulatory subunits.
• Tissue Specificity: Highly expressed in heart and brain, in particular in cortex, cerebellum, amygdala and caudate nucleus. Detected at lower levels in liver, skeletal muscle, kidney and pancreas. Isoform 1 predominates in most tissues. Isoform 1 and isoform 2 are detected at similar levels in brain, skeletal muscle and pancreas.
• KEGG Pathway: Spinocerebellar ataxia (hsa05017)
• 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

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Spinocerebellar ataxia type 19/22	DIS7TVX7	Strong	Autosomal dominant	[1]
Brugada syndrome 1	DISKBA7V	Disputed	Autosomal dominant	[2]
Brugada syndrome 9	DIS6HGXF	Limited	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Potassium voltage-gated channel subfamily D member 3 (KCND3).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Potassium voltage-gated channel subfamily D member 3 (KCND3).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Potassium voltage-gated channel subfamily D member 3 (KCND3).	[5]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Potassium voltage-gated channel subfamily D member 3 (KCND3).	[6]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Potassium voltage-gated channel subfamily D member 3 (KCND3).	[7]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Potassium voltage-gated channel subfamily D member 3 (KCND3).	[6]
Fluoxetine	DM3PD2C	Approved	Fluoxetine decreases the activity of Potassium voltage-gated channel subfamily D member 3 (KCND3).	[8]
Verapamil	DMA7PEW	Phase 2/3 Trial	Verapamil decreases the activity of Potassium voltage-gated channel subfamily D member 3 (KCND3).	[9]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate decreases the activity of Potassium voltage-gated channel subfamily D member 3 (KCND3).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Potassium voltage-gated channel subfamily D member 3 (KCND3).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Potassium voltage-gated channel subfamily D member 3 (KCND3).	[12]

References

• [1] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [5] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [6] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [7] 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.
• [8] Establishment of ion channel and ABC transporter assays in 3D-cultured ReNcell VM on a 384-pillar plate for neurotoxicity potential. Toxicol In Vitro. 2022 Aug;82:105375. doi: 10.1016/j.tiv.2022.105375. Epub 2022 May 10.
• [9] hKv4.3 channel characterization and regulation by calcium channel antagonists. Biochem Biophys Res Commun. 2001 Feb 23;281(2):452-60. doi: 10.1006/bbrc.2001.4396.
• [10] Mechanism of alpha-adrenergic regulation of expressed hKv4.3 currents. Am J Physiol Heart Circ Physiol. 2001 Dec;281(6):H2518-27. doi: 10.1152/ajpheart.2001.281.6.H2518.
• [11] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [12] 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.