Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5J7HVM)

• DOT Name: Short transient receptor potential channel 6 (TRPC6)
• Synonyms: TrpC6; Transient receptor protein 6; TRP-6
• Gene Name: TRPC6
• Related Disease:
  Focal segmental glomerulosclerosis 2
  Familial idiopathic steroid-resistant nephrotic syndrome
• UniProt ID: TRPC6_HUMAN
• PDB ID: 5YX9; 6UZ8; 6UZA; 7A6U; 7DXF; 7DXG
• Pfam ID: PF12796 ; PF00520 ; PF08344
• Sequence:
  MSQSPAFGPRRGSSPRGAAGAAARRNESQDYLLMDSELGEDGCPQAPLPCYGYYPCFRGS
  DNRLAHRRQTVLREKGRRLANRGPAYMFSDRSTSLSIEEERFLDAAEYGNIPVVRKMLEE
  CHSLNVNCVDYMGQNALQLAVANEHLEITELLLKKENLSRVGDALLLAISKGYVRIVEAI
  LSHPAFAEGKRLATSPSQSELQQDDFYAYDEDGTRFSHDVTPIILAAHCQEYEIVHTLLR
  KGARIERPHDYFCKCNDCNQKQKHDSFSHSRSRINAYKGLASPAYLSLSSEDPVMTALEL
  SNELAVLANIEKEFKNDYKKLSMQCKDFVVGLLDLCRNTEEVEAILNGDVETLQSGDHGR
  PNLSRLKLAIKYEVKKFVAHPNCQQQLLSIWYENLSGLRQQTMAVKFLVVLAVAIGLPFL
  ALIYWFAPCSKMGKIMRGPFMKFVAHAASFTIFLGLLVMNAADRFEGTKLLPNETSTDNA
  KQLFRMKTSCFSWMEMLIISWVIGMIWAECKEIWTQGPKEYLFELWNMLDFGMLAIFAAS
  FIARFMAFWHASKAQSIIDANDTLKDLTKVTLGDNVKYYNLARIKWDPSDPQIISEGLYA
  IAVVLSFSRIAYILPANESFGPLQISLGRTVKDIFKFMVIFIMVFVAFMIGMFNLYSYYI
  GAKQNEAFTTVEESFKTLFWAIFGLSEVKSVVINYNHKFIENIGYVLYGVYNVTMVIVLL
  NMLIAMINSSFQEIEDDADVEWKFARAKLWFSYFEEGRTLPVPFNLVPSPKSLFYLLLKL
  KKWISELFQGHKKGFQEDAEMNKINEEKKLGILGSHEDLSKLSLDKKQVGHNKQPSIRSS
  EDFHLNSFNNPPRQYQKIMKRLIKRYVLQAQIDKESDEVNEGELKEIKQDISSLRYELLE
  EKSQNTEDLAELIRELGEKLSMEPNQEETNR
• Function: Thought to form a receptor-activated non-selective calcium permeant cation channel. Probably is operated by a phosphatidylinositol second messenger system activated by receptor tyrosine kinases or G-protein coupled receptors. Activated by diacylglycerol (DAG) in a membrane-delimited fashion, independently of protein kinase C. Seems not to be activated by intracellular calcium store depletion.
• Tissue Specificity: Expressed primarily in placenta, lung, spleen, ovary and small intestine. Expressed in podocytes and is a component of the glomerular slit diaphragm.
• KEGG Pathway:
  cGMP-PKG sig.ling pathway (hsa04022)
  Axon guidance (hsa04360)
• Reactome Pathway:
  Elevation of cytosolic Ca2+ levels (R-HSA-139853)
  TRP channels (R-HSA-3295583)
  Role of second messengers in netrin-1 signaling (R-HSA-418890)
  Effects of PIP2 hydrolysis (R-HSA-114508)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Focal segmental glomerulosclerosis 2	DISAIHPT	Strong	Autosomal dominant	[1]
Familial idiopathic steroid-resistant nephrotic syndrome	DISQ53RS	Supportive	Autosomal dominant	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Short transient receptor potential channel 6 (TRPC6).	[3]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Short transient receptor potential channel 6 (TRPC6).	[4]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Short transient receptor potential channel 6 (TRPC6).	[5]
Flufenamic Acid	DMC8VNH	Approved	Flufenamic Acid increases the activity of Short transient receptor potential channel 6 (TRPC6).	[6]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Short transient receptor potential channel 6 (TRPC6).	[5]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Short transient receptor potential channel 6 (TRPC6).	[8]
AA-861	DMPEB0Z	Terminated	AA-861 decreases the activity of Short transient receptor potential channel 6 (TRPC6).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Short transient receptor potential channel 6 (TRPC6).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Short transient receptor potential channel 6 (TRPC6).	[8]

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 increases the methylation of Short transient receptor potential channel 6 (TRPC6).	[7]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis. Science. 2005 Jun 17;308(5729):1801-4. doi: 10.1126/science.1106215. Epub 2005 May 5.
• [3] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [4] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [5] 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.
• [6] Evidence of a role for TRPC channels in VEGF-mediated increased vascular permeability in vivo. Am J Physiol Heart Circ Physiol. 2004 Mar;286(3):H1015-26. doi: 10.1152/ajpheart.00826.2003. Epub 2003 Oct 9.
• [7] 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.
• [8] 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.
• [9] The role of transient receptor potential channel blockers in human gastric cancer cell viability. Can J Physiol Pharmacol. 2012 Feb;90(2):175-86. doi: 10.1139/y11-114. Epub 2012 Feb 6.
• [10] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.