Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWMAV6G)

• DOT Name: Potassium channel subfamily K member 3 (KCNK3)
• Synonyms: Acid-sensitive potassium channel protein TASK-1; TWIK-related acid-sensitive K(+) channel 1; Two pore potassium channel KT3.1; Two pore K(+) channel KT3.1
• Gene Name: KCNK3
• Related Disease:
  Pulmonary arterial hypertension
  Pulmonary hypertension, primary, 4
  Heritable pulmonary arterial hypertension
• UniProt ID: KCNK3_HUMAN
• PDB ID: 6RV2; 6RV3; 6RV4
• Pfam ID: PF07885
• Sequence:
  MKRQNVRTLALIVCTFTYLLVGAAVFDALESEPELIERQRLELRQQELRARYNLSQGGYE
  ELERVVLRLKPHKAGVQWRFAGSFYFAITVITTIGYGHAAPSTDGGKVFCMFYALLGIPL
  TLVMFQSLGERINTLVRYLLHRAKKGLGMRRADVSMANMVLIGFFSCISTLCIGAAAFSH
  YEHWTFFQAYYYCFITLTTIGFGDYVALQKDQALQTQPQYVAFSFVYILTGLTVIGAFLN
  LVVLRFMTMNAEDEKRDAEHRALLTRNGQAGGGGGGGSAHTTDTASSTAAAGGGGFRNVY
  AEVLHFQSMCSCLWYKSREKLQYSIPMIIPRDLSTSDTCVEQSHSSPGGGGRYSDTPSRR
  CLCSGAPRSAISSVSTGLHSLSTFRGLMKRRSSV
• Function: pH-dependent, voltage-insensitive, background potassium channel protein. Rectification direction results from potassium ion concentration on either side of the membrane. Acts as an outward rectifier when external potassium concentration is low. When external potassium concentration is high, current is inward.
• Tissue Specificity: Widespread expression in adult. Strongest expression in pancreas and placenta. Lower expression in brain, lung, prostate, heart, kidney, uterus, small intestine and colon.
• KEGG Pathway:
  Aldosterone synthesis and secretion (hsa04925)
  Cortisol synthesis and secretion (hsa04927)
  Cushing syndrome (hsa04934)
• Reactome Pathway:
  Phase 4 - resting membrane potential (R-HSA-5576886)
  TWIK-releated acid-sensitive K+ channel (TASK) (R-HSA-1299316)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Pulmonary arterial hypertension	DISP8ZX5	Definitive	Autosomal dominant	[1]
Pulmonary hypertension, primary, 4	DISXV14P	Strong	Autosomal dominant	[2]
Heritable pulmonary arterial hypertension	DISD1Y94	Supportive	Autosomal dominant	[2]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Riociguat	DMXBLMP	Approved	Potassium channel subfamily K member 3 (KCNK3) decreases the response to substance of Riociguat.	[14]

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 Potassium channel subfamily K member 3 (KCNK3).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Potassium channel subfamily K member 3 (KCNK3).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Potassium channel subfamily K member 3 (KCNK3).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Potassium channel subfamily K member 3 (KCNK3).	[5]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Potassium channel subfamily K member 3 (KCNK3).	[6]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Potassium channel subfamily K member 3 (KCNK3).	[7]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Potassium channel subfamily K member 3 (KCNK3).	[8]
Paclitaxel	DMLB81S	Approved	Paclitaxel increases the expression of Potassium channel subfamily K member 3 (KCNK3).	[9]
Carvedilol	DMHTEAO	Approved	Carvedilol decreases the activity of Potassium channel subfamily K member 3 (KCNK3).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Potassium channel subfamily K member 3 (KCNK3).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Potassium channel subfamily K member 3 (KCNK3).	[13]

References

• [1] 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.
• [2] A novel channelopathy in pulmonary arterial hypertension. N Engl J Med. 2013 Jul 25;369(4):351-361. doi: 10.1056/NEJMoa1211097.
• [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] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [5] Functional cardiotoxicity assessment of cosmetic compounds using human-induced pluripotent stem cell-derived cardiomyocytes. Arch Toxicol. 2018 Jan;92(1):371-381.
• [6] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [7] Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer. BMC Cancer. 2007 Dec 11;7:223.
• [8] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [9] Proteomic analysis of anti-cancer effects by paclitaxel treatment in cervical cancer cells. Gynecol Oncol. 2005 Jul;98(1):45-53. doi: 10.1016/j.ygyno.2005.04.010.
• [10] Carvedilol targets human K2P 3.1 (TASK1) K+ leak channels. Br J Pharmacol. 2011 Jul;163(5):1099-110. doi: 10.1111/j.1476-5381.2011.01319.x.
• [11] 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.
• [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.
• [13] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [14] Characterization and regulation of wild-type and mutant TASK-1 two pore domain potassium channels indicated in pulmonary arterial hypertension. J Physiol. 2019 Feb;597(4):1087-1101. doi: 10.1113/JP277275. Epub 2018 Nov 24.