Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT354X8E)

• DOT Name: Transient receptor potential cation channel subfamily M member 4 (TRPM4)
• Synonyms: hTRPM4; Calcium-activated non-selective cation channel 1; Long transient receptor potential channel 4; LTrpC-4; LTrpC4; Melastatin-4
• Gene Name: TRPM4
• Related Disease:
  Erythrokeratodermia variabilis et progressiva 6
  Progressive familial heart block type IB
  Erythrokeratodermia variabilis
  Progressive familial heart block
  Brugada syndrome
• UniProt ID: TRPM4_HUMAN
• PDB ID: 5WP6; 6BQR; 6BQV; 6BWI
• Pfam ID: PF00520 ; PF18139
• Sequence:
  MVVPEKEQSWIPKIFKKKTCTTFIVDSTDPGGTLCQCGRPRTAHPAVAMEDAFGAAVVTV
  WDSDAHTTEKPTDAYGELDFTGAGRKHSNFLRLSDRTDPAAVYSLVTRTWGFRAPNLVVS
  VLGGSGGPVLQTWLQDLLRRGLVRAAQSTGAWIVTGGLHTGIGRHVGVAVRDHQMASTGG
  TKVVAMGVAPWGVVRNRDTLINPKGSFPARYRWRGDPEDGVQFPLDYNYSAFFLVDDGTH
  GCLGGENRFRLRLESYISQQKTGVGGTGIDIPVLLLLIDGDEKMLTRIENATQAQLPCLL
  VAGSGGAADCLAETLEDTLAPGSGGARQGEARDRIRRFFPKGDLEVLQAQVERIMTRKEL
  LTVYSSEDGSEEFETIVLKALVKACGSSEASAYLDELRLAVAWNRVDIAQSELFRGDIQW
  RSFHLEASLMDALLNDRPEFVRLLISHGLSLGHFLTPMRLAQLYSAAPSNSLIRNLLDQA
  SHSAGTKAPALKGGAAELRPPDVGHVLRMLLGKMCAPRYPSGGAWDPHPGQGFGESMYLL
  SDKATSPLSLDAGLGQAPWSDLLLWALLLNRAQMAMYFWEMGSNAVSSALGACLLLRVMA
  RLEPDAEEAARRKDLAFKFEGMGVDLFGECYRSSEVRAARLLLRRCPLWGDATCLQLAMQ
  ADARAFFAQDGVQSLLTQKWWGDMASTTPIWALVLAFFCPPLIYTRLITFRKSEEEPTRE
  ELEFDMDSVINGEGPVGTADPAEKTPLGVPRQSGRPGCCGGRCGGRRCLRRWFHFWGAPV
  TIFMGNVVSYLLFLLLFSRVLLVDFQPAPPGSLELLLYFWAFTLLCEELRQGLSGGGGSL
  ASGGPGPGHASLSQRLRLYLADSWNQCDLVALTCFLLGVGCRLTPGLYHLGRTVLCIDFM
  VFTVRLLHIFTVNKQLGPKIVIVSKMMKDVFFFLFFLGVWLVAYGVATEGLLRPRDSDFP
  SILRRVFYRPYLQIFGQIPQEDMDVALMEHSNCSSEPGFWAHPPGAQAGTCVSQYANWLV
  VLLLVIFLLVANILLVNLLIAMFSYTFGKVQGNSDLYWKAQRYRLIREFHSRPALAPPFI
  VISHLRLLLRQLCRRPRSPQPSSPALEHFRVYLSKEAERKLLTWESVHKENFLLARARDK
  RESDSERLKRTSQKVDLALKQLGHIREYEQRLKVLEREVQQCSRVLGWVAEALSRSALLP
  PGGPPPPDLPGSKD
• Function: Calcium-activated non selective (CAN) cation channel that mediates membrane depolarization. While it is activated by increase in intracellular Ca(2+), it is impermeable to it. Mediates transport of monovalent cations (Na(+) > K(+) > Cs(+) > Li(+)), leading to depolarize the membrane. It thereby plays a central role in cadiomyocytes, neurons from entorhinal cortex, dorsal root and vomeronasal neurons, endocrine pancreas cells, kidney epithelial cells, cochlea hair cells etc. Participates in T-cell activation by modulating Ca(2+) oscillations after T lymphocyte activation, which is required for NFAT-dependent IL2 production. Involved in myogenic constriction of cerebral arteries. Controls insulin secretion in pancreatic beta-cells. May also be involved in pacemaking or could cause irregular electrical activity under conditions of Ca(2+) overload. Affects T-helper 1 (Th1) and T-helper 2 (Th2) cell motility and cytokine production through differential regulation of calcium signaling and NFATC1 localization. Enhances cell proliferation through up-regulation of the beta-catenin signaling pathway. Plays a role in keratinocyte differentiation.
• Tissue Specificity: Widely expressed with a high expression in intestine and prostate. In brain, it is both expressed in whole cerebral arteries and isolated vascular smooth muscle cells. Prominently expressed in Purkinje fibers. Expressed at higher levels in T-helper 2 (Th2) cells as compared to T-helper 1 (Th1) cells. Expressed in keratocytes .
• KEGG Pathway: Insulin secretion (hsa04911)
• Reactome Pathway:
  Sensory perception of sweet, bitter, and umami (glutamate) taste (R-HSA-9717207)
  TRP channels (R-HSA-3295583)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Erythrokeratodermia variabilis et progressiva 6	DISD8E4P	Strong	Autosomal dominant	[1]
Progressive familial heart block type IB	DISF3V8H	Strong	Autosomal dominant	[2]
Erythrokeratodermia variabilis	DIS4BMUQ	Supportive	Autosomal dominant	[1]
Progressive familial heart block	DISNEF3B	Supportive	Autosomal dominant	[2]
Brugada syndrome	DISSGN0E	Disputed	Autosomal dominant	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Transient receptor potential cation channel subfamily M member 4 (TRPM4).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Transient receptor potential cation channel subfamily M member 4 (TRPM4).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Transient receptor potential cation channel subfamily M member 4 (TRPM4).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Transient receptor potential cation channel subfamily M member 4 (TRPM4).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Transient receptor potential cation channel subfamily M member 4 (TRPM4).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Transient receptor potential cation channel subfamily M member 4 (TRPM4).	[9]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Transient receptor potential cation channel subfamily M member 4 (TRPM4).	[10]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Transient receptor potential cation channel subfamily M member 4 (TRPM4).	[11]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Transient receptor potential cation channel subfamily M member 4 (TRPM4).	[12]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Transient receptor potential cation channel subfamily M member 4 (TRPM4).	[13]
Aspirin	DM672AH	Approved	Aspirin increases the expression of Transient receptor potential cation channel subfamily M member 4 (TRPM4).	[14]
Aldosterone	DM9S2JW	Approved	Aldosterone increases the expression of Transient receptor potential cation channel subfamily M member 4 (TRPM4).	[9]
L-glutamic acid	DM4PUDW	Approved	L-glutamic acid increases the activity of Transient receptor potential cation channel subfamily M member 4 (TRPM4).	[15]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Transient receptor potential cation channel subfamily M member 4 (TRPM4).	[16]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Transient receptor potential cation channel subfamily M member 4 (TRPM4).	[17]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Transient receptor potential cation channel subfamily M member 4 (TRPM4).	[18]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Transient receptor potential cation channel subfamily M member 4 (TRPM4).	[20]
Manganese	DMKT129	Investigative	Manganese increases the expression of Transient receptor potential cation channel subfamily M member 4 (TRPM4).	[21]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Transient receptor potential cation channel subfamily M member 4 (TRPM4).	[19]

References

• [1] Gain-of-Function Mutations in TRPM4 Activation Gate Cause Progressive Symmetric Erythrokeratodermia. J Invest Dermatol. 2019 May;139(5):1089-1097. doi: 10.1016/j.jid.2018.10.044. Epub 2018 Dec 5.
• [2] Impaired endocytosis of the ion channel TRPM4 is associated with human progressive familial heart block type I. J Clin Invest. 2009 Sep;119(9):2737-44. doi: 10.1172/JCI38292. Epub 2009 Aug 24.
• [3] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [4] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [5] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [6] 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.
• [7] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [8] Transient receptor potential melastatin 4 contributes to early-stage endothelial injury induced by arsenic trioxide. Toxicol Lett. 2019 Sep 15;312:98-108. doi: 10.1016/j.toxlet.2019.04.035. Epub 2019 May 1.
• [9] Transient Receptor Potential Melastatin 4 (TRPM4) Contributes to High Salt Diet-Mediated Early-Stage Endothelial Injury. Cell Physiol Biochem. 2017;41(2):835-848. doi: 10.1159/000459695. Epub 2017 Feb 16.
• [10] 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.
• [11] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [12] Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011 Jul;26(7):1813-25.
• [13] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [14] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [15] Depletion of 14-3-3 reduces the surface expression of Transient Receptor Potential Melastatin 4b (TRPM4b) channels and attenuates TRPM4b-mediated glutamate-induced neuronal cell death. Mol Brain. 2014 Jul 22;7:52. doi: 10.1186/s13041-014-0052-3.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] 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.
• [18] 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.
• [19] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [20] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [21] 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.