Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ0LGNO)

• DOT Name: Transient receptor potential cation channel subfamily V member 6 (TRPV6)
• Synonyms: TrpV6; CaT-like; CaT-L; Calcium transport protein 1; CaT1; Epithelial calcium channel 2; ECaC2
• Gene Name: TRPV6
• Related Disease:
  Intestinal hypomagnesemia 1
  Hyperparathyroidism, transient neonatal
  Neonatal severe primary hyperparathyroidism
• UniProt ID: TRPV6_HUMAN
• PDB ID: 6BO8; 6BO9; 6BOA; 6D7S; 6D7T; 6E2F; 7K4A; 7K4B; 7K4C; 7K4D; 7K4E; 7K4F; 7S88; 7S89; 7S8B; 7S8C; 8FOA; 8FOB; 8SP8
• Pfam ID: PF00023 ; PF12796 ; PF00520
• Sequence:
  MGPLQGDGGPALGGADVAPRLSPVRVWPRPQAPKEPALHPMGLSLPKEKGLILCLWSKFC
  RWFQRRESWAQSRDEQNLLQQKRIWESPLLLAAKDNDVQALNKLLKYEDCKVHQRGAMGE
  TALHIAALYDNLEAAMVLMEAAPELVFEPMTSELYEGQTALHIAVVNQNMNLVRALLARR
  ASVSARATGTAFRRSPCNLIYFGEHPLSFAACVNSEEIVRLLIEHGADIRAQDSLGNTVL
  HILILQPNKTFACQMYNLLLSYDRHGDHLQPLDLVPNHQGLTPFKLAGVEGNTVMFQHLM
  QKRKHTQWTYGPLTSTLYDLTEIDSSGDEQSLLELIITTKKREARQILDQTPVKELVSLK
  WKRYGRPYFCMLGAIYLLYIICFTMCCIYRPLKPRTNNRTSPRDNTLLQQKLLQEAYMTP
  KDDIRLVGELVTVIGAIIILLVEVPDIFRMGVTRFFGQTILGGPFHVLIITYAFMVLVTM
  VMRLISASGEVVPMSFALVLGWCNVMYFARGFQMLGPFTIMIQKMIFGDLMRFCWLMAVV
  ILGFASAFYIIFQTEDPEELGHFYDYPMALFSTFELFLTIIDGPANYNVDLPFMYSITYA
  AFAIIATLLMLNLLIAMMGDTHWRVAHERDELWRAQIVATTVMLERKLPRCLWPRSGICG
  REYGLGDRWFLRVEDRQDLNRQRIQRYAQAFHTRGSEDLDKDSVEKLELGCPFSPHLSLP
  MPSVSRSTSRSSANWERLRQGTLRRDLRGIINRGLEDGESWEYQI
• Function: Calcium selective cation channel that mediates Ca(2+) uptake in various tissues, including the intestine. Important for normal Ca(2+) ion homeostasis in the body, including bone and skin. The channel is activated by low internal calcium level, probably including intracellular calcium store depletion, and the current exhibits an inward rectification. Inactivation includes both a rapid Ca(2+)-dependent and a slower Ca(2+)-calmodulin-dependent mechanism; the latter may be regulated by phosphorylation. In vitro, is slowly inhibited by Mg(2+) in a voltage-independent manner. Heteromeric assembly with TRPV5 seems to modify channel properties. TRPV5-TRPV6 heteromultimeric concatemers exhibit voltage-dependent gating.
• Tissue Specificity: Expressed at high levels in the gastrointestinal tract, including esophagus, stomach, duodenum, jejunum, ileum and colon, and in pancreas, placenta, prostate and salivary gland. Expressed at moderate levels in liver, kidney and testis. Expressed in trophoblasts of placenta villus trees (at protein level). Expressed in locally advanced prostate cancer, metastatic and androgen-insensitive prostatic lesions but not detected in healthy prostate tissue and benign prostatic hyperplasia.
• KEGG Pathway:
  Salivary secretion (hsa04970)
  Mineral absorption (hsa04978)
• Reactome Pathway: TRP channels (R-HSA-3295583)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intestinal hypomagnesemia 1	DISKMKFJ	Strong	Autosomal recessive	[1]
Hyperparathyroidism, transient neonatal	DISGEJ3Q	Moderate	Autosomal recessive	[2]
Neonatal severe primary hyperparathyroidism	DISOJ4ON	Supportive	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Capsaicin	DMGMF6V	Approved	Transient receptor potential cation channel subfamily V member 6 (TRPV6) increases the response to substance of Capsaicin.	[12]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Manganese	DMKT129	Investigative	Transient receptor potential cation channel subfamily V member 6 (TRPV6) increases the uptake of Manganese.	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Transient receptor potential cation channel subfamily V member 6 (TRPV6).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Transient receptor potential cation channel subfamily V member 6 (TRPV6).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Transient receptor potential cation channel subfamily V member 6 (TRPV6).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Transient receptor potential cation channel subfamily V member 6 (TRPV6).	[4]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Transient receptor potential cation channel subfamily V member 6 (TRPV6).	[5]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Transient receptor potential cation channel subfamily V member 6 (TRPV6).	[6]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Transient receptor potential cation channel subfamily V member 6 (TRPV6).	[7]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Transient receptor potential cation channel subfamily V member 6 (TRPV6).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Transient receptor potential cation channel subfamily V member 6 (TRPV6).	[10]

References

• [1] TRPV6 Variants Interfere with Maternal-Fetal Calcium Transport through the Placenta and Cause Transient Neonatal Hyperparathyroidism. Am J Hum Genet. 2018 Jun 7;102(6):1104-1114. doi: 10.1016/j.ajhg.2018.04.006. Epub 2018 May 31.
• [2] 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.
• [3] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [4] Vitamin D receptor-mediated upregulation of CYP3A4 and MDR1 by quercetin in Caco-2 cells. Planta Med. 2016 Jan;82(1-2):121-30.
• [5] 1,25-Dihydroxyvitamin D and 25-hydroxyvitamin D--mediated regulation of TRPV6 (a putative epithelial calcium channel) mRNA expression in Caco-2 cells. Eur J Nutr. 2006 Jun;45(4):196-204. doi: 10.1007/s00394-005-0586-3. Epub 2005 Dec 21.
• [6] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [7] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [8] Functional gene expression profile underlying methotrexate-induced senescence in human colon cancer cells. Tumour Biol. 2011 Oct;32(5):965-76.
• [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] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [11] 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.
• [12] TRPV6 mediates capsaicin-induced apoptosis in gastric cancer cells--Mechanisms behind a possible new "hot" cancer treatment. Biochim Biophys Acta. 2007 Apr;1773(4):565-76. doi: 10.1016/j.bbamcr.2007.01.001. Epub 2007 Jan 10.
• [13] Heavy metal cations permeate the TRPV6 epithelial cation channel. Cell Calcium. 2011 Jan;49(1):43-55. doi: 10.1016/j.ceca.2010.11.007. Epub 2010 Dec 13.