Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7ACGYK)

• DOT Name: Transient receptor potential cation channel subfamily M member 8 (TRPM8)
• Synonyms: Long transient receptor potential channel 6; LTrpC-6; LTrpC6; Transient receptor potential p8; Trp-p8
• Gene Name: TRPM8
• UniProt ID: TRPM8_HUMAN
• PDB ID: 8BDC
• Pfam ID: PF00520 ; PF18139
• Sequence:
  MSFRAARLSMRNRRNDTLDSTRTLYSSASRSTDLSYSESDLVNFIQANFKKRECVFFTKD
  SKATENVCKCGYAQSQHMEGTQINQSEKWNYKKHTKEFPTDAFGDIQFETLGKKGKYIRL
  SCDTDAEILYELLTQHWHLKTPNLVISVTGGAKNFALKPRMRKIFSRLIYIAQSKGAWIL
  TGGTHYGLMKYIGEVVRDNTISRSSEENIVAIGIAAWGMVSNRDTLIRNCDAEGYFLAQY
  LMDDFTRDPLYILDNNHTHLLLVDNGCHGHPTVEAKLRNQLEKYISERTIQDSNYGGKIP
  IVCFAQGGGKETLKAINTSIKNKIPCVVVEGSGQIADVIASLVEVEDALTSSAVKEKLVR
  FLPRTVSRLPEEETESWIKWLKEILECSHLLTVIKMEEAGDEIVSNAISYALYKAFSTSE
  QDKDNWNGQLKLLLEWNQLDLANDEIFTNDRRWESADLQEVMFTALIKDRPKFVRLFLEN
  GLNLRKFLTHDVLTELFSNHFSTLVYRNLQIAKNSYNDALLTFVWKLVANFRRGFRKEDR
  NGRDEMDIELHDVSPITRHPLQALFIWAILQNKKELSKVIWEQTRGCTLAALGASKLLKT
  LAKVKNDINAAGESEELANEYETRAVELFTECYSSDEDLAEQLLVYSCEAWGGSNCLELA
  VEATDQHFIAQPGVQNFLSKQWYGEISRDTKNWKIILCLFIIPLVGCGFVSFRKKPVDKH
  KKLLWYYVAFFTSPFVVFSWNVVFYIAFLLLFAYVLLMDFHSVPHPPELVLYSLVFVLFC
  DEVRQWYVNGVNYFTDLWNVMDTLGLFYFIAGIVFRLHSSNKSSLYSGRVIFCLDYIIFT
  LRLIHIFTVSRNLGPKIIMLQRMLIDVFFFLFLFAVWMVAFGVARQGILRQNEQRWRWIF
  RSVIYEPYLAMFGQVPSDVDGTTYDFAHCTFTGNESKPLCVELDEHNLPRFPEWITIPLV
  CIYMLSTNILLVNLLVAMFGYTVGTVQENNDQVWKFQRYFLVQEYCSRLNIPFPFIVFAY
  FYMVVKKCFKCCCKEKNMESSVCCFKNEDNETLAWEGVMKENYLVKINTKANDTSEEMRH
  RFRQLDTKLNDLKGLLKEIANKIK
• Function: Receptor-activated non-selective cation channel involved in detection of sensations such as coolness, by being activated by cold temperature below 25 degrees Celsius. Activated by icilin, eucalyptol, menthol, cold and modulation of intracellular pH. Involved in menthol sensation. Permeable for monovalent cations sodium, potassium, and cesium and divalent cation calcium. Temperature sensing is tightly linked to voltage-dependent gating. Activated upon depolarization, changes in temperature resulting in graded shifts of its voltage-dependent activation curves. The chemical agonist menthol functions as a gating modifier, shifting activation curves towards physiological membrane potentials. Temperature sensitivity arises from a tenfold difference in the activation energies associated with voltage-dependent opening and closing. In prostate cancer cells, shows strong inward rectification and high calcium selectivity in contrast to its behavior in normal cells which is characterized by outward rectification and poor cationic selectivity. Plays a role in prostate cancer cell migration. Isoform 2 and isoform 3 negatively regulate menthol- and cold-induced channel activity by stabilizing the closed state of the channel.
• Tissue Specificity: Expressed in prostate. Also expressed in prostate tumors and in non-prostatic primary tumors such as colon, lung, breast and skin tumors.
• KEGG Pathway: Inflammatory mediator regulation of TRP channels (hsa04750)
• Reactome Pathway: TRP channels (R-HSA-3295583)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Menthol	DMG2KW7	Approved	Transient receptor potential cation channel subfamily M member 8 (TRPM8) decreases the response to substance of Menthol.	[10]
Praziquantel	DMOU1PK	Approved	Transient receptor potential cation channel subfamily M member 8 (TRPM8) decreases the response to substance of Praziquantel.	[10]

14 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 Transient receptor potential cation channel subfamily M member 8 (TRPM8).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Transient receptor potential cation channel subfamily M member 8 (TRPM8).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Transient receptor potential cation channel subfamily M member 8 (TRPM8).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Transient receptor potential cation channel subfamily M member 8 (TRPM8).	[4]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Transient receptor potential cation channel subfamily M member 8 (TRPM8).	[5]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Transient receptor potential cation channel subfamily M member 8 (TRPM8).	[6]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of Transient receptor potential cation channel subfamily M member 8 (TRPM8).	[7]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Transient receptor potential cation channel subfamily M member 8 (TRPM8).	[8]
Permethrin	DMZ0Q1G	Approved	Permethrin decreases the expression of Transient receptor potential cation channel subfamily M member 8 (TRPM8).	[9]
Capsaicin	DMGMF6V	Approved	Capsaicin increases the activity of Transient receptor potential cation channel subfamily M member 8 (TRPM8).	[10]
Enzalutamide	DMGL19D	Approved	Enzalutamide decreases the expression of Transient receptor potential cation channel subfamily M member 8 (TRPM8).	[11]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Transient receptor potential cation channel subfamily M member 8 (TRPM8).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Transient receptor potential cation channel subfamily M member 8 (TRPM8).	[13]
BCTC	DMT5AGJ	Investigative	BCTC decreases the activity of Transient receptor potential cation channel subfamily M member 8 (TRPM8).	[10]

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 Transient receptor potential cation channel subfamily M member 8 (TRPM8).	[12]

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] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [3] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [4] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [5] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [6] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [7] Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. Toxicol Appl Pharmacol. 2009 Feb 1;234(3):345-60.
• [8] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [9] 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.
• [10] The anthelminthic drug praziquantel is a selective agonist of the sensory transient receptor potential melastatin type 8 channel. Toxicol Appl Pharmacol. 2017 Dec 1;336:55-65. doi: 10.1016/j.taap.2017.10.012. Epub 2017 Oct 18.
• [11] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [12] 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.
• [13] 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.