Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT93GC7V)

• DOT Name: Potassium channel subfamily K member 10 (KCNK10)
• Synonyms: Outward rectifying potassium channel protein TREK-2; TREK-2 K(+) channel subunit
• Gene Name: KCNK10
• Related Disease:
  Epilepsy
  Major depressive disorder
  Mental disorder
  Neuralgia
  Status epilepticus seizure
  Migraine disorder
• UniProt ID: KCNKA_HUMAN
• PDB ID: 4BW5; 4XDJ; 4XDK; 4XDL
• Pfam ID: PF07885
• Sequence:
  MFFLYTDFFLSLVAVPAAAPVCQPKSATNGQPPAPAPTPTPRLSISSRATVVARMEGTSQ
  GGLQTVMKWKTVVAIFVVVVVYLVTGGLVFRALEQPFESSQKNTIALEKAEFLRDHVCVS
  PQELETLIQHALDADNAGVSPIGNSSNNSSHWDLGSAFFFAGTVITTIGYGNIAPSTEGG
  KIFCILYAIFGIPLFGFLLAGIGDQLGTIFGKSIARVEKVFRKKQVSQTKIRVISTILFI
  LAGCIVFVTIPAVIFKYIEGWTALESIYFVVVTLTTVGFGDFVAGGNAGINYREWYKPLV
  WFWILVGLAYFAAVLSMIGDWLRVLSKKTKEEVGEIKAHAAEWKANVTAEFRETRRRLSV
  EIHDKLQRAATIRSMERRRLGLDQRAHSLDMLSPEKRSVFAALDTGRFKASSQESINNRP
  NNLRLKGPEQLNKHGQGASEDNIINKFGSTSRLTKRKNKDLKKTLPEDVQKIYKTFRNYS
  LDEEKKEEETEKMCNSDNSSTAMLTDCIQQHAELENGMIPTDTKDREPENNSLLEDRN
• Function: Outward rectifying potassium channel. Produces rapidly activating and non-inactivating outward rectifier K(+) currents. Activated by arachidonic acid and other naturally occurring unsaturated free fatty acids.
• Tissue Specificity: Abundantly expressed in pancreas and kidney and to a lower level in brain, testis, colon, and small intestine. Isoform b is strongly expressed in kidney (primarily in the proximal tubule) and pancreas, whereas isoform c is abundantly expressed in brain.
• KEGG Pathway: Gastric acid secretion (hsa04971)
• Reactome Pathway:
  Phase 4 - resting membrane potential (R-HSA-5576886)
  TWIK related potassium channel (TREK) (R-HSA-1299503)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epilepsy	DISBB28L	Strong	Altered Expression	[1]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[2]
Mental disorder	DIS3J5R8	Strong	Biomarker	[3]
Neuralgia	DISWO58J	Strong	Biomarker	[4]
Status epilepticus seizure	DISY3BIC	Strong	Altered Expression	[1]
Migraine disorder	DISFCQTG	Disputed	Biomarker	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Potassium channel subfamily K member 10 (KCNK10).	[6]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Potassium channel subfamily K member 10 (KCNK10).	[8]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Potassium channel subfamily K member 10 (KCNK10).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Potassium channel subfamily K member 10 (KCNK10).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Potassium channel subfamily K member 10 (KCNK10).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Potassium channel subfamily K member 10 (KCNK10).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Potassium channel subfamily K member 10 (KCNK10).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Potassium channel subfamily K member 10 (KCNK10).	[11]

References

• [1] miRNA-187-3p-Mediated Regulation of the KCNK10/TREK-2 Potassium Channel in a Rat Epilepsy Model.ACS Chem Neurosci. 2016 Nov 16;7(11):1585-1594. doi: 10.1021/acschemneuro.6b00222. Epub 2016 Sep 22.
• [2] Activation of TREK-1, but Not TREK-2, Channel by Mood Stabilizers.Int J Mol Sci. 2017 Nov 19;18(11):2460. doi: 10.3390/ijms18112460.
• [3] The association of DNA methylation and brain volume in healthy individuals and schizophrenia patients.Schizophr Res. 2015 Dec;169(1-3):447-452. doi: 10.1016/j.schres.2015.08.035. Epub 2015 Sep 14.
• [4] Recent advance and possible future in TREK-2: a two-pore potassium channel may involved in the process of NPP, brain ischemia and memory impairment.Med Hypotheses. 2008;70(3):618-24. doi: 10.1016/j.mehy.2007.06.016. Epub 2007 Aug 6.
• [5] Migraine-Associated TRESK Mutations Increase Neuronal Excitability through Alternative Translation Initiation and Inhibition of TREK.Neuron. 2019 Jan 16;101(2):232-245.e6. doi: 10.1016/j.neuron.2018.11.039. Epub 2018 Dec 17.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [8] 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.
• [9] 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.
• [10] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [11] 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.
• [12] 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.