Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWBT8MG)

• DOT Name: Potassium channel subfamily K member 2 (KCNK2)
• Synonyms: Outward rectifying potassium channel protein TREK-1; TREK-1 K(+) channel subunit; Two pore domain potassium channel TREK-1; Two pore potassium channel TPKC1
• Gene Name: KCNK2
• UniProt ID: KCNK2_HUMAN
• PDB ID: 4TWK
• Pfam ID: PF07885
• Sequence:
  MLPSASRERPGYRAGVAAPDLLDPKSAAQNSKPRLSFSTKPTVLASRVESDTTINVMKWK
  TVSTIFLVVVLYLIIGATVFKALEQPHEISQRTTIVIQKQTFISQHSCVNSTELDELIQQ
  IVAAINAGIIPLGNTSNQISHWDLGSSFFFAGTVITTIGFGNISPRTEGGKIFCIIYALL
  GIPLFGFLLAGVGDQLGTIFGKGIAKVEDTFIKWNVSQTKIRIISTIIFILFGCVLFVAL
  PAIIFKHIEGWSALDAIYFVVITLTTIGFGDYVAGGSDIEYLDFYKPVVWFWILVGLAYF
  AAVLSMIGDWLRVISKKTKEEVGEFRAHAAEWTANVTAEFKETRRRLSVEIYDKFQRATS
  IKRKLSAELAGNHNQELTPCRRTLSVNHLTSERDVLPPLLKTESIYLNGLTPHCAGEEIA
  VIENIK
• Function: Ion channel that contributes to passive transmembrane potassium transport. Reversibly converts between a voltage-insensitive potassium leak channel and a voltage-dependent outward rectifying potassium channel in a phosphorylation-dependent manner. In astrocytes, forms mostly heterodimeric potassium channels with KCNK1, with only a minor proportion of functional channels containing homodimeric KCNK2. In astrocytes, the heterodimer formed by KCNK1 and KCNK2 is required for rapid glutamate release in response to activation of G-protein coupled receptors, such as F2R and CNR1; [Isoform 4]: Does not display channel activity but reduces the channel activity of isoform 1 and isoform 2 and reduces cell surface expression of isoform 2.
• Tissue Specificity: Isoform 4 is detected in kidney, adrenal gland and brain where it is preferentially expressed in the amygdala but not found in thalamus, hypothalamus, hippocampus or substantia nigra.
• KEGG Pathway:
  cAMP sig.ling pathway (hsa04024)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  Cortisol synthesis and secretion (hsa04927)
  Cushing syndrome (hsa04934)
  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

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Camptothecin	DM6CHNJ	Phase 3	Potassium channel subfamily K member 2 (KCNK2) decreases the response to substance of Camptothecin.	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Potassium channel subfamily K member 2 (KCNK2).	[1]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Potassium channel subfamily K member 2 (KCNK2).	[2]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Potassium channel subfamily K member 2 (KCNK2).	[3]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Potassium channel subfamily K member 2 (KCNK2).	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Potassium channel subfamily K member 2 (KCNK2).	[4]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Potassium channel subfamily K member 2 (KCNK2).	[6]

References

• [1] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [2] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [3] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [4] 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.
• [5] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [6] 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.
• [7] ATR inhibitors VE-821 and VX-970 sensitize cancer cells to topoisomerase i inhibitors by disabling DNA replication initiation and fork elongation responses. Cancer Res. 2014 Dec 1;74(23):6968-79.