Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT11KYA8)

• DOT Name: Small conductance calcium-activated potassium channel protein 3 (KCNN3)
• Synonyms: SK3; SKCa 3; SKCa3; KCa2.3
• Gene Name: KCNN3
• Related Disease:
  Zimmermann-laband syndrome 3
  Zimmermann-Laband syndrome
  Schizophrenia
• UniProt ID: KCNN3_HUMAN
• Pfam ID: PF02888 ; PF07885 ; PF03530
• Sequence:
  MDTSGHFHDSGVGDLDEDPKCPCPSSGDEQQQQQQQQQQQQPPPPAPPAAPQQPLGPSLQ
  PQPPQLQQQQQQQQQQQQQQPPHPLSQLAQLQSQPVHPGLLHSSPTAFRAPPSSNSTAIL
  HPSSRQGSQLNLNDHLLGHSPSSTATSGPGGGSRHRQASPLVHRRDSNPFTEIAMSSCKY
  SGGVMKPLSRLSASRRNLIEAETEGQPLQLFSPSNPPEIVISSREDNHAHQTLLHHPNAT
  HNHQHAGTTASSTTFPKANKRKNQNIGYKLGHRRALFEKRKRLSDYALIFGMFGIVVMVI
  ETELSWGLYSKDSMFSLALKCLISLSTIILLGLIIAYHTREVQLFVIDNGADDWRIAMTY
  ERILYISLEMLVCAIHPIPGEYKFFWTARLAFSYTPSRAEADVDIILSIPMFLRLYLIAR
  VMLLHSKLFTDASSRSIGALNKINFNTRFVMKTLMTICPGTVLLVFSISLWIIAAWTVRV
  CERYHDQQDVTSNFLGAMWLISITFLSIGYGDMVPHTYCGKGVCLLTGIMGAGCTALVVA
  VVARKLELTKAEKHVHNFMMDTQLTKRIKNAAANVLRETWLIYKHTKLLKKIDHAKVRKH
  QRKFLQAIHQLRSVKMEQRKLSDQANTLVDLSKMQNVMYDLITELNDRSEDLEKQIGSLE
  SKLEHLTASFNSLPLLIADTLRQQQQQLLSAIIEARGVSVAVGTTHTPISDSPIGVSSTS
  FPTPYTSSSSC
• Function: Forms a voltage-independent potassium channel activated by intracellular calcium. Activation is followed by membrane hyperpolarization. Thought to regulate neuronal excitability by contributing to the slow component of synaptic afterhyperpolarization.
• KEGG Pathway:
  Insulin secretion (hsa04911)
  GnRH secretion (hsa04929)
• Reactome Pathway: Ca2+ activated K+ channels (R-HSA-1296052)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Zimmermann-laband syndrome 3	DISY7ARC	Strong	Autosomal dominant	[1]
Zimmermann-Laband syndrome	DISXXVYH	Supportive	Autosomal recessive	[1]
Schizophrenia	DISSRV2N	Limited	Unknown	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Small conductance calcium-activated potassium channel protein 3 (KCNN3).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Small conductance calcium-activated potassium channel protein 3 (KCNN3).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Small conductance calcium-activated potassium channel protein 3 (KCNN3).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Small conductance calcium-activated potassium channel protein 3 (KCNN3).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Small conductance calcium-activated potassium channel protein 3 (KCNN3).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Small conductance calcium-activated potassium channel protein 3 (KCNN3).	[7]
Marinol	DM70IK5	Approved	Marinol increases the expression of Small conductance calcium-activated potassium channel protein 3 (KCNN3).	[8]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Small conductance calcium-activated potassium channel protein 3 (KCNN3).	[9]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Small conductance calcium-activated potassium channel protein 3 (KCNN3).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Small conductance calcium-activated potassium channel protein 3 (KCNN3).	[12]

References

• [1] Gain-of-Function Mutations in KCNN3 Encoding the Small-Conductance Ca(2+)-Activated K(+) Channel SK3 Cause Zimmermann-Laband Syndrome. Am J Hum Genet. 2019 Jun 6;104(6):1139-1157. doi: 10.1016/j.ajhg.2019.04.012. Epub 2019 May 30.
• [2] Mutation screening of the KCNN3 gene reveals a rare frameshift mutation. Mol Psychiatry. 2001 May;6(3):259-60. doi: 10.1038/sj.mp.4000128.
• [3] 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.
• [4] Atrial-like Engineered Heart Tissue: An In?Vitro Model of the Human Atrium. Stem Cell Reports. 2018 Dec 11;11(6):1378-1390. doi: 10.1016/j.stemcr.2018.10.008. Epub 2018 Nov 8.
• [5] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [9] 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.
• [10] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [11] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [12] 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.