Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDE1FT0)

• DOT Name: G protein-activated inward rectifier potassium channel 2 (KCNJ6)
• Synonyms: GIRK-2; BIR1; Inward rectifier K(+) channel Kir3.2; KATP-2; Potassium channel, inwardly rectifying subfamily J member 6
• Gene Name: KCNJ6
• Related Disease: Keppen-Lubinsky syndrome
• UniProt ID: KCNJ6_HUMAN
• Pfam ID: PF01007 ; PF17655
• Sequence:
  MAKLTESMTNVLEGDSMDQDVESPVAIHQPKLPKQARDDLPRHISRDRTKRKIQRYVRKD
  GKCNVHHGNVRETYRYLTDIFTTLVDLKWRFNLLIFVMVYTVTWLFFGMIWWLIAYIRGD
  MDHIEDPSWTPCVTNLNGFVSAFLFSIETETTIGYGYRVITDKCPEGIILLLIQSVLGSI
  VNAFMVGCMFVKISQPKKRAETLVFSTHAVISMRDGKLCLMFRVGDLRNSHIVEASIRAK
  LIKSKQTSEGEFIPLNQTDINVGYYTGDDRLFLVSPLIISHEINQQSPFWEISKAQLPKE
  ELEIVVILEGMVEATGMTCQARSSYITSEILWGYRFTPVLTLEDGFYEVDYNSFHETYET
  STPSLSAKELAELASRAELPLSWSVSSKLNQHAELETEEEEKNLEEQTERNGDVANLENE
  SKV
• Function: This potassium channel may be involved in the regulation of insulin secretion by glucose and/or neurotransmitters acting through G-protein-coupled receptors. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium.
• Tissue Specificity: Most abundant in cerebellum, and to a lesser degree in islets and exocrine pancreas.
• KEGG Pathway:
  Circadian entrainment (hsa04713)
  Retrograde endocan.binoid sig.ling (hsa04723)
  Cholinergic sy.pse (hsa04725)
  Serotonergic sy.pse (hsa04726)
  GABAergic sy.pse (hsa04727)
  Dopaminergic sy.pse (hsa04728)
  Estrogen sig.ling pathway (hsa04915)
  Oxytocin sig.ling pathway (hsa04921)
  GnRH secretion (hsa04929)
  Morphine addiction (hsa05032)
• Reactome Pathway:
  Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits (R-HSA-997272)
  Activation of G protein gated Potassium channels (R-HSA-1296041)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Keppen-Lubinsky syndrome	DISADE3A	Strong	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of G protein-activated inward rectifier potassium channel 2 (KCNJ6).	[2]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of G protein-activated inward rectifier potassium channel 2 (KCNJ6).	[3]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of G protein-activated inward rectifier potassium channel 2 (KCNJ6).	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of G protein-activated inward rectifier potassium channel 2 (KCNJ6).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of G protein-activated inward rectifier potassium channel 2 (KCNJ6).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of G protein-activated inward rectifier potassium channel 2 (KCNJ6).	[4]

References

• [1] Expanding the spectrum of KCNJ6-related disorders: Milder phenotype with pathological startle responses. Clin Genet. 2023 Jan;103(1):103-108. doi: 10.1111/cge.14226. Epub 2022 Sep 15.
• [2] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [3] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [4] 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.
• [5] Transcriptional profiling in the human prefrontal cortex: evidence for two activational states associated with cocaine abuse. Pharmacogenomics J. 2003;3(1):27-40.
• [6] 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.