Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHQG16J)

• DOT Name: G protein-activated inward rectifier potassium channel 1 (KCNJ3)
• Synonyms: GIRK-1; Inward rectifier K(+) channel Kir3.1; Potassium channel, inwardly rectifying subfamily J member 3
• Gene Name: KCNJ3
• UniProt ID: KCNJ3_HUMAN
• Pfam ID: PF01007 ; PF17655
• Sequence:
  MSALRRKFGDDYQVVTTSSSGSGLQPQGPGQDPQQQLVPKKKRQRFVDKNGRCNVQHGNL
  GSETSRYLSDLFTTLVDLKWRWNLFIFILTYTVAWLFMASMWWVIAYTRGDLNKAHVGNY
  TPCVANVYNFPSAFLFFIETEATIGYGYRYITDKCPEGIILFLFQSILGSIVDAFLIGCM
  FIKMSQPKKRAETLMFSEHAVISMRDGKLTLMFRVGNLRNSHMVSAQIRCKLLKSRQTPE
  GEFLPLDQLELDVGFSTGADQLFLVSPLTICHVIDAKSPFYDLSQRSMQTEQFEIVVILE
  GIVETTGMTCQARTSYTEDEVLWGHRFFPVISLEEGFFKVDYSQFHATFEVPTPPYSVKE
  QEEMLLMSSPLIAPAITNSKERHNSVECLDGLDDITTKLPSKLQKITGREDFPKKLLRMS
  STTSEKAYSLGDLPMKLQRISSVPGNSEEKLVSKTTKMLSDPMSQSVADLPPKLQKMAGG
  AARMEGNLPAKLRKMNSDRFT
• Function: This potassium channel is controlled by G proteins. 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. This receptor plays a crucial role in regulating the heartbeat.
• KEGG Pathway:
  Circadian entrainment (hsa04713)
  Retrograde endocan.binoid sig.ling (hsa04723)
  Glutamatergic sy.pse (hsa04724)
  Cholinergic sy.pse (hsa04725)
  Serotonergic sy.pse (hsa04726)
  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

This DOT Affected the Drug Response of 5 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Haloperidol	DM96SE0	Approved	G protein-activated inward rectifier potassium channel 1 (KCNJ3) increases the Seizures (incl subtypes) ADR of Haloperidol.	[11]
Thioridazine	DM35M8J	Approved	G protein-activated inward rectifier potassium channel 1 (KCNJ3) increases the Seizures (incl subtypes) ADR of Thioridazine.	[11]
Clonidine	DM6RZ9Q	Approved	G protein-activated inward rectifier potassium channel 1 (KCNJ3) increases the Seizures (incl subtypes) ADR of Clonidine.	[11]
Pimozide	DMW83TP	Approved	G protein-activated inward rectifier potassium channel 1 (KCNJ3) increases the Seizures (incl subtypes) ADR of Pimozide.	[11]
NAPQI	DM8F5LR	Investigative	G protein-activated inward rectifier potassium channel 1 (KCNJ3) affects the response to substance of NAPQI.	[12]

10 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 G protein-activated inward rectifier potassium channel 1 (KCNJ3).	[1]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of G protein-activated inward rectifier potassium channel 1 (KCNJ3).	[2]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of G protein-activated inward rectifier potassium channel 1 (KCNJ3).	[3]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of G protein-activated inward rectifier potassium channel 1 (KCNJ3).	[4]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of G protein-activated inward rectifier potassium channel 1 (KCNJ3).	[5]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol decreases the expression of G protein-activated inward rectifier potassium channel 1 (KCNJ3).	[6]
Propranolol	DM79NTF	Approved	Propranolol increases the expression of G protein-activated inward rectifier potassium channel 1 (KCNJ3).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of G protein-activated inward rectifier potassium channel 1 (KCNJ3).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of G protein-activated inward rectifier potassium channel 1 (KCNJ3).	[9]
Manganese	DMKT129	Investigative	Manganese increases the expression of G protein-activated inward rectifier potassium channel 1 (KCNJ3).	[10]

References

• [1] 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.
• [2] 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.
• [3] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [4] 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.
• [5] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [6] The genomic response of a human uterine endometrial adenocarcinoma cell line to 17alpha-ethynyl estradiol. Toxicol Sci. 2009 Jan;107(1):40-55.
• [7] Expression of inwardly rectifying potassium channels (GIRKs) and beta-adrenergic regulation of breast cancer cell lines. BMC Cancer. 2004 Dec 16;4:93. doi: 10.1186/1471-2407-4-93.
• [8] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [9] 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.
• [10] Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.
• [11] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [12] Acetaminophen-NAPQI hepatotoxicity: a cell line model system genome-wide association study. Toxicol Sci. 2011 Mar;120(1):33-41. doi: 10.1093/toxsci/kfq375. Epub 2010 Dec 22.