Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPUFK4C)

• DOT Name: Calsyntenin-3 (CLSTN3)
• Synonyms: Alcadein-beta; Alc-beta
• Gene Name: CLSTN3
• Related Disease:
  Alzheimer disease
  Amyloidosis
  Hyperaldosteronism
  Matthew-Wood syndrome
  Parkinson disease
  Schizophrenia
  Follicular lymphoma
• UniProt ID: CSTN3_HUMAN
• Pfam ID: PF19699
• Sequence:
  MTLLLLPLLLASLLASCSCNKANKHKPWIEAEYQGIVMENDNTVLLNPPLFALDKDAPLR
  YAGEICGFRLHGSGVPFEAVILDKATGEGLIRAKEPVDCEAQKEHTFTIQAYDCGEGPDG
  ANTKKSHKATVHVRVNDVNEFAPVFVERLYRAAVTEGKLYDRILRVEAIDGDCSPQYSQI
  CYYEILTPNTPFLIDNDGNIENTEKLQYSGERLYKFTVTAYDCGKKRAADDAEVEIQVKP
  TCKPSWQGWNKRIEYAPGAGSLALFPGIRLETCDEPLWNIQATIELQTSHVAKGCDRDNY
  SERALRKLCGAATGEVDLLPMPGPNANWTAGLSVHYSQDSSLIYWFNGTQAVQVPLGGPS
  GLGSGPQDSLSDHFTLSFWMKHGVTPNKGKKEEETIVCNTVQNEDGFSHYSLTVHGCRIA
  FLYWPLLESARPVKFLWKLEQVCDDEWHHYALNLEFPTVTLYTDGISFDPALIHDNGLIH
  PPRREPALMIGACWTEEKNKEKEKGDNSTDTTQGDPLSIHHYFHGYLAGFSVRSGRLESR
  EVIECLYACREGLDYRDFESLGKGMKVHVNPSQSLLTLEGDDVETFNHALQHVAYMNTLR
  FATPGVRPLRLTTAVKCFSEESCVSIPEVEGYVVVLQPDAPQILLSGTAHFARPAVDFEG
  TNGVPLFPDLQITCSISHQVEAKKDESWQGTVTDTRMSDEIVHNLDGCEISLVGDDLDPE
  RESLLLDTTSLQQRGLELTNTSAYLTIAGVESITVYEEILRQARYRLRHGAALYTRKFRL
  SCSEMNGRYSSNEFIVEVNVLHSMNRVAHPSHVLSSQQFLHRGHQPPPEMAGHSLASSHR
  NSMIPSAATLIIVVCVGFLVLMVVLGLVRIHSLHRRVSGAGGPPGASSDPKDPDLFWDDS
  ALTIIVNPMESYQNRQSCVTGAVGGQQEDEDSSDSEVADSPSSDERRIIETPPHRY
• Function: Postsynaptic adhesion molecule that binds to presynaptic neurexins to mediate both excitatory and inhibitory synapse formation. Promotes synapse development by acting as a cell adhesion molecule at the postsynaptic membrane, which associates with both neurexin-alpha and neurexin-beta proteins at the presynaptic membrane. Regulates the balance between excitatory and inhibitory synapses by inhibiting formation of excitatory parallel-fiber synapses and promoting formation of inhibitory synapses in the same neuron. May also be involved in ascorbate (vitamin C) uptake via its interaction with SLC23A2/SVCT2. Complex formation with APBA2 and APP, stabilizes APP metabolism and enhances APBA2-mediated suppression of beta-APP40 secretion, due to the retardation of intracellular APP maturation (Probable); [Isoform CLSTN3beta]: Adipose-specific isoform that plays a key role in adaptive thermogenesis. Facilitates the efficient use of stored triglyceride by promoting multilocular morphology of thermogenic adipocytes: acts by inhibiting the activity of CIDEA and CIDEC on lipid droplets, thereby preventing lipid droplet fusion and facilitating lipid utilization. May also participate in adaptive thermogenesis by promoting sympathetic innervation of thermogenic adipose tissue: acts by driving secretion of neurotrophic factor S100B from brown adipocytes, stimulating neurite outgrowth from sympathetic neurons.
• Tissue Specificity: According to PubMed:12498782, expressed predominantly in the brain and in kidney . Low levels in heart, skeletal muscle, liver, placenta, pancreas and lung . According to PubMed:12972431, predominant expression in brain, and only marginal in kidney . In brain, present throughout all cortical layers, highest levels in GABAergic neurons (based on morphology and distribution pattern) .; [Isoform CLSTN3beta]: Expression is restricted to adipose tissue, with high expression in multilocular thermogenic adipocytes (brown adipose tissue).

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Altered Expression	[1]
Amyloidosis	DISHTAI2	Strong	Biomarker	[2]
Hyperaldosteronism	DIS3WGAL	Strong	Biomarker	[3]
Matthew-Wood syndrome	DISA7HR7	Strong	Biomarker	[4]
Parkinson disease	DISQVHKL	Strong	Biomarker	[5]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[6]
Follicular lymphoma	DISVEUR6	Limited	Genetic Variation	[7]

9 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 Calsyntenin-3 (CLSTN3).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Calsyntenin-3 (CLSTN3).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Calsyntenin-3 (CLSTN3).	[10]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Calsyntenin-3 (CLSTN3).	[11]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Calsyntenin-3 (CLSTN3).	[12]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Calsyntenin-3 (CLSTN3).	[13]
Rigosertib	DMOSTXF	Phase 3	Rigosertib affects the expression of Calsyntenin-3 (CLSTN3).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Calsyntenin-3 (CLSTN3).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Calsyntenin-3 (CLSTN3).	[17]

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 Calsyntenin-3 (CLSTN3).	[15]

References

• [1] Decrease in p3-Alc37 and p3-Alc40, products of Alcadein generated by -secretase cleavages, in aged monkeys and patients with Alzheimer's disease.Alzheimers Dement (N Y). 2019 Nov 7;5:740-750. doi: 10.1016/j.trci.2019.09.015. eCollection 2019.
• [2] The role of calsyntenin-3 in dystrophic neurite formation in Alzheimer's disease brain.Geriatr Gerontol Int. 2016 Mar;16 Suppl 1:43-50. doi: 10.1111/ggi.12737.
• [3] Genetic characterization of a mouse line with primary aldosteronism.J Mol Endocrinol. 2017 Feb;58(2):67-78. doi: 10.1530/JME-16-0200. Epub 2016 Dec 13.
• [4] Should platinum-based chemotherapy be preferred for germline BReast CAncer genes (BRCA) 1 and 2-mutated pancreatic ductal adenocarcinoma (PDAC) patients? A systematic review and meta-analysis.Cancer Treat Rev. 2019 Nov;80:101895. doi: 10.1016/j.ctrv.2019.101895. Epub 2019 Sep 6.
• [5] Integrated Analysis of Whole Exome Sequencing and Copy Number Evaluation in Parkinson's Disease.Sci Rep. 2019 Mar 4;9(1):3344. doi: 10.1038/s41598-019-40102-x.
• [6] Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect.Schizophr Bull. 2019 Jun 18;45(4):824-834. doi: 10.1093/schbul/sby140.
• [7] Follicular lymphoma frequently originates in the salivary gland.Pathol Int. 2006 Oct;56(10):576-83. doi: 10.1111/j.1440-1827.2006.02011.x.
• [8] 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.
• [9] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [10] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [11] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [12] 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.
• [13] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [14] ON 01910.Na is selectively cytotoxic for chronic lymphocytic leukemia cells through a dual mechanism of action involving PI3K/AKT inhibition and induction of oxidative stress. Clin Cancer Res. 2012 Apr 1;18(7):1979-91. doi: 10.1158/1078-0432.CCR-11-2113. Epub 2012 Feb 20.
• [15] 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.
• [16] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [17] Involvement of the Endocrine-Disrupting Chemical Bisphenol A (BPA) in Human Placentation. J Clin Med. 2020 Feb 3;9(2):405. doi: 10.3390/jcm9020405.