Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTE4CDOQ)

• DOT Name: Transient receptor potential cation channel subfamily M member 3 (TRPM3)
• Synonyms: Long transient receptor potential channel 3; LTrpC-3; LTrpC3; Melastatin-2; MLSN2
• Gene Name: TRPM3
• Related Disease:
  Cataract 50 with or without glaucoma
  Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures
  Autosomal dominant non-syndromic intellectual disability
  Cataract-glaucoma syndrome
  Intellectual disability
  Schizophrenia
• UniProt ID: TRPM3_HUMAN
• Pfam ID: PF00520 ; PF18139 ; PF16519
• Sequence:
  MPEPWGTVYFLGIAQVFSFLFSWWNLEGVMNQADAPRPLNWTIRKLCHAAFLPSVRLLKA
  QKSWIERAFYKRECVHIIPSTKDPHRCCCGRLIGQHVGLTPSISVLQNEKNESRLSRNDI
  QSEKWSISKHTQLSPTDAFGTIEFQGGGHSNKAMYVRVSFDTKPDLLLHLMTKEWQLELP
  KLLISVHGGLQNFELQPKLKQVFGKGLIKAAMTTGAWIFTGGVNTGVIRHVGDALKDHAS
  KSRGKICTIGIAPWGIVENQEDLIGRDVVRPYQTMSNPMSKLTVLNSMHSHFILADNGTT
  GKYGAEVKLRRQLEKHISLQKINTRCLPFFSLDSRLFYSFWGSCQLDSVGIGQGVPVVAL
  IVEGGPNVISIVLEYLRDTPPVPVVVCDGSGRASDILAFGHKYSEEGGLINESLRDQLLV
  TIQKTFTYTRTQAQHLFIILMECMKKKELITVFRMGSEGHQDIDLAILTALLKGANASAP
  DQLSLALAWNRVDIARSQIFIYGQQWPVGSLEQAMLDALVLDRVDFVKLLIENGVSMHRF
  LTISRLEELYNTRHGPSNTLYHLVRDVKKGNLPPDYRISLIDIGLVIEYLMGGAYRCNYT
  RKRFRTLYHNLFGPKRPKALKLLGMEDDIPLRRGRKTTKKREEEVDIDLDDPEINHFPFP
  FHELMVWAVLMKRQKMALFFWQHGEEAMAKALVACKLCKAMAHEASENDMVDDISQELNH
  NSRDFGQLAVELLDQSYKQDEQLAMKLLTYELKNWSNATCLQLAVAAKHRDFIAHTCSQM
  LLTDMWMGRLRMRKNSGLKVILGILLPPSILSLEFKNKDDMPYMSQAQEIHLQEKEAEEP
  EKPTKEKEEEDMELTAMLGRNNGESSRKKDEEEVQSKHRLIPLGRKIYEFYNAPIVKFWF
  YTLAYIGYLMLFNYIVLVKMERWPSTQEWIVISYIFTLGIEKMREILMSEPGKLLQKVKV
  WLQEYWNVTDLIAILLFSVGMILRLQDQPFRSDGRVIYCVNIIYWYIRLLDIFGVNKYLG
  PYVMMIGKMMIDMMYFVIIMLVVLMSFGVARQAILFPNEEPSWKLAKNIFYMPYWMIYGE
  VFADQIDPPCGQNETREDGKIIQLPPCKTGAWIVPAIMACYLLVANILLVNLLIAVFNNT
  FFEVKSISNQVWKFQRYQLIMTFHERPVLPPPLIIFSHMTMIFQHLCCRWRKHESDPDER
  DYGLKLFITDDELKKVHDFEEQCIEEYFREKDDRFNSSNDERIRVTSERVENMSMRLEEV
  NEREHSMKASLQTVDIRLAQLEDLIGRMATALERLTGLERAESNKIRSRTSSDCTDAAYI
  VRQSSFNSQEGNTFKLQESIDPAGEETMSPTSPTLMPRMRSHSFYSVNMKDKGGIEKLES
  IFKERSLSLHRATSSHSVAKEPKAPAAPANTLAIVPDSRRPSSCIDIYVSAMDELHCDID
  PLDNSVNILGLGEPSFSTPVPSTAPSSSAYATLAPTDRPPSRSIDFEDITSMDTRSFSSD
  YTHLPECQNPWDSEPPMYHTIERSKSSRYLATTPFLLEEAPIVKSHSFMFSPSRSYYANF
  GVPVKTAEYTSITDCIDTRCVNAPQAIADRAAFPGGLGDKVEDLTCCHPEREAELSHPSS
  DSEENEAKGRRATIAISSQEGDNSERTLSNNITVPKIERANSYSAEEPSAPYAHTRKSFS
  ISDKLDRQRNTASLRNPFQRSKSSKPEGRGDSLSMRRLSRTSAFQSFESKHN
• Function: Calcium channel mediating constitutive calcium ion entry. Its activity is increased by reduction in extracellular osmolarity, by store depletion and muscarinic receptor activation. In addition, forms heteromultimeric ion channels with TRPM1 which are permeable for calcium and zinc ions.
• Tissue Specificity: Expressed primarily in the kidney and, at lower levels, in brain, testis, ovary, pancreas and spinal cord. Expression in the brain and kidney was determined at protein level. In the kidney, expressed predominantly in the collecting tubular epithelium in the medulla, medullary rays, and periglomerular regions; in the brain, highest levels are found in the cerebellum, choroid plexus, the locus coeruleus, the posterior thalamus and the substantia nigra. Down-regulated in renal tumors compared to normal kidney. Expressed in the lens .
• Reactome Pathway: TRP channels (R-HSA-3295583)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cataract 50 with or without glaucoma	DISGWGJ9	Strong	Autosomal dominant	[1]
Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures	DISBYMG4	Strong	Autosomal dominant	[2]
Autosomal dominant non-syndromic intellectual disability	DISD6L06	Supportive	Autosomal dominant	[3]
Cataract-glaucoma syndrome	DISHZK8E	Limited	Autosomal dominant	[2]
Intellectual disability	DISMBNXP	Limited	Autosomal dominant	[2]
Schizophrenia	DISSRV2N	Limited	Autosomal dominant	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methamphetamine	DMPM4SK	Approved	Transient receptor potential cation channel subfamily M member 3 (TRPM3) affects the response to substance of Methamphetamine.	[15]

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 Transient receptor potential cation channel subfamily M member 3 (TRPM3).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Transient receptor potential cation channel subfamily M member 3 (TRPM3).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Transient receptor potential cation channel subfamily M member 3 (TRPM3).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Transient receptor potential cation channel subfamily M member 3 (TRPM3).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Transient receptor potential cation channel subfamily M member 3 (TRPM3).	[8]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Transient receptor potential cation channel subfamily M member 3 (TRPM3).	[9]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Transient receptor potential cation channel subfamily M member 3 (TRPM3).	[10]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Transient receptor potential cation channel subfamily M member 3 (TRPM3).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Transient receptor potential cation channel subfamily M member 3 (TRPM3).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Transient receptor potential cation channel subfamily M member 3 (TRPM3).	[14]

2 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 affects the methylation of Transient receptor potential cation channel subfamily M member 3 (TRPM3).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Transient receptor potential cation channel subfamily M member 3 (TRPM3).	[13]

References

• [1] Mutation of the melastatin-related cation channel, TRPM3, underlies inherited cataract and glaucoma. PLoS One. 2014 Aug 4;9(8):e104000. doi: 10.1371/journal.pone.0104000. eCollection 2014.
• [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] De novo substitutions of TRPM3 cause intellectual disability and epilepsy. Eur J Hum Genet. 2019 Oct;27(10):1611-1618. doi: 10.1038/s41431-019-0462-x. Epub 2019 Jul 5.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Cyclosporine A--induced oxidative stress in human renal mesangial cells: a role for ERK 1/2 MAPK signaling. Toxicol Sci. 2012 Mar;126(1):101-13.
• [6] 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.
• [7] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [8] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [9] 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.
• [10] 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.
• [11] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [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] 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.
• [14] 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.
• [15] Genome-wide association for methamphetamine dependence: convergent results from 2 samples. Arch Gen Psychiatry. 2008 Mar;65(3):345-55. doi: 10.1001/archpsyc.65.3.345.