Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYY9DPV)

• DOT Name: Short transient receptor potential channel 4 (TRPC4)
• Synonyms: TrpC4; Trp-related protein 4; hTrp-4; hTrp4
• Gene Name: TRPC4
• UniProt ID: TRPC4_HUMAN
• Pfam ID: PF00023 ; PF12796 ; PF00520 ; PF08344
• Sequence:
  MAQFYYKRNVNAPYRDRIPLRIVRAESELSPSEKAYLNAVEKGDYASVKKSLEEAEIYFK
  ININCIDPLGRTALLIAIENENLELIELLLSFNVYVGDALLHAIRKEVVGAVELLLNHKK
  PSGEKQVPPILLDKQFSEFTPDITPIILAAHTNNYEIIKLLVQKGVSVPRPHEVRCNCVE
  CVSSSDVDSLRHSRSRLNIYKALASPSLIALSSEDPFLTAFQLSWELQELSKVENEFKSE
  YEELSRQCKQFAKDLLDQTRSSRELEIILNYRDDNSLIEEQSGNDLARLKLAIKYRQKEF
  VAQPNCQQLLASRWYDEFPGWRRRHWAVKMVTCFIIGLLFPVFSVCYLIAPKSPLGLFIR
  KPFIKFICHTASYLTFLFLLLLASQHIDRSDLNRQGPPPTIVEWMILPWVLGFIWGEIKQ
  MWDGGLQDYIHDWWNLMDFVMNSLYLATISLKIVAFVKYSALNPRESWDMWHPTLVAEAL
  FAIANIFSSLRLISLFTANSHLGPLQISLGRMLLDILKFLFIYCLVLLAFANGLNQLYFY
  YEETKGLTCKGIRCEKQNNAFSTLFETLQSLFWSIFGLINLYVTNVKAQHEFTEFVGATM
  FGTYNVISLVVLLNMLIAMMNNSYQLIADHADIEWKFARTKLWMSYFEEGGTLPTPFNVI
  PSPKSLWYLIKWIWTHLCKKKMRRKPESFGTIGRRAADNLRRHHQYQEVMRNLVKRYVAA
  MIRDAKTEEGLTEENFKELKQDISSFRFEVLGLLRGSKLSTIQSANASKESSNSADSDEK
  SDSEGNSKDKKKNFSLFDLTTLIHPRSAAIASERHNISNGSALVVQEPPREKQRKVNFVT
  DIKNFGLFHRRSKQNAAEQNANQIFSVSEEVARQQAAGPLERNIQLESRGLASRGDLSIP
  GLSEQCVLVDHRERNTDTLGLQVGKRVCPFKSEKVVVEDTVPIIPKEKHAKEEDSSIDYD
  LNLPDTVTHEDYVTTRL
• Function: Forms a receptor-activated non-selective calcium permeant cation channel. Acts as a cell-cell contact-dependent endothelial calcium entry channel. Probably operated by a phosphatidylinositol second messenger system activated by receptor tyrosine kinases or G-protein coupled receptors. Mediates cation entry, with an enhanced permeability to barium over calcium. May also be activated by intracellular calcium store depletion.
• Tissue Specificity: Strongly expressed in placenta. Expressed at lower levels in heart, pancreas, kidney and brain. Expressed in endothelial cells. Isoform alpha was found to be the predominant isoform. Isoform beta was not found in pancreas and brain.
• KEGG Pathway:
  Axon guidance (hsa04360)
  GnRH secretion (hsa04929)
• Reactome Pathway:
  Role of second messengers in netrin-1 signaling (R-HSA-418890)
  TRP channels (R-HSA-3295583)

Molecular Interaction Atlas (MIA) of This DOT

10 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 Short transient receptor potential channel 4 (TRPC4).	[1]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Short transient receptor potential channel 4 (TRPC4).	[2]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Short transient receptor potential channel 4 (TRPC4).	[3]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Short transient receptor potential channel 4 (TRPC4).	[4]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Short transient receptor potential channel 4 (TRPC4).	[5]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Short transient receptor potential channel 4 (TRPC4).	[6]
Malathion	DMXZ84M	Approved	Malathion decreases the expression of Short transient receptor potential channel 4 (TRPC4).	[7]
Carbachol	DMX9K8F	Approved	Carbachol increases the activity of Short transient receptor potential channel 4 (TRPC4).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Short transient receptor potential channel 4 (TRPC4).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Short transient receptor potential channel 4 (TRPC4).	[11]

1 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 decreases the methylation of Short transient receptor potential channel 4 (TRPC4).	[9]

References

• [1] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [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] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [4] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [5] 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.
• [6] 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.
• [7] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [8] Activation of TRPV3 by Wood Smoke Particles and Roles in Pneumotoxicity. Chem Res Toxicol. 2018 May 21;31(5):291-301. doi: 10.1021/acs.chemrestox.7b00336. Epub 2018 Apr 30.
• [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] 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.
• [11] 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.