Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6JHAWM)

• DOT Name: Neuronal calcium sensor 1 (NCS1)
• Synonyms: NCS-1; Frequenin homolog; Frequenin-like protein; Frequenin-like ubiquitous protein
• Gene Name: NCS1
• Related Disease:
  Autism
  Bipolar disorder
  Wolfram syndrome
  X-linked intellectual disability
  Alzheimer disease
  Cerebral infarction
  Cognitive impairment
  Depression
  Fragile X syndrome
  Lung squamous cell carcinoma
  Mental disorder
  Non-insulin dependent diabetes
  Obesity
  Substance abuse
  Anxiety disorder
  Arrhythmia
  Breast cancer
  Breast carcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Cocaine addiction
  Hepatocellular carcinoma
  Liver cancer
  Metastatic malignant neoplasm
  Neoplasm
  Nervous system disease
  Neuroblastoma
  Schizophrenia
• UniProt ID: NCS1_HUMAN
• PDB ID: 1G8I; 2LCP; 4GUK; 5O9S; 6QI4
• Pfam ID: PF00036 ; PF13499
• Sequence:
  MGKSNSKLKPEVVEELTRKTYFTEKEVQQWYKGFIKDCPSGQLDAAGFQKIYKQFFPFGD
  PTKFATFVFNVFDENKDGRIEFSEFIQALSVTSRGTLDEKLRWAFKLYDLDNDGYITRNE
  MLDIVDAIYQMVGNTVELPEEENTPEKRVDRIFAMMDKNADGKLTLQEFQEGSKADPSIV
  QALSLYDGLV
• Function: Neuronal calcium sensor, regulator of G protein-coupled receptor phosphorylation in a calcium dependent manner. Directly regulates GRK1 (RHOK), but not GRK2 to GRK5. Can substitute for calmodulin. Stimulates PI4KB kinase activity. Involved in long-term synaptic plasticity through its interaction with PICK1. May also play a role in neuron differentiation through inhibition of the activity of N-type voltage-gated calcium channel.

Molecular Interaction Atlas (MIA) of This DOT

27 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism	DISV4V1Z	Definitive	Biomarker	[1]
Bipolar disorder	DISAM7J2	Definitive	Biomarker	[2]
Wolfram syndrome	DISN16XW	Definitive	Biomarker	[3]
X-linked intellectual disability	DISYJBY3	Definitive	Biomarker	[4]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[5]
Cerebral infarction	DISR1WNP	Strong	Biomarker	[6]
Cognitive impairment	DISH2ERD	Strong	Biomarker	[7]
Depression	DIS3XJ69	Strong	Biomarker	[8]
Fragile X syndrome	DISE8W3A	Strong	Biomarker	[9]
Lung squamous cell carcinoma	DISXPIBD	Strong	Altered Expression	[10]
Mental disorder	DIS3J5R8	Strong	Biomarker	[11]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[11]
Obesity	DIS47Y1K	Strong	Biomarker	[11]
Substance abuse	DIS327VW	Strong	Altered Expression	[12]
Anxiety disorder	DISBI2BT	Limited	Biomarker	[13]
Arrhythmia	DISFF2NI	Limited	Biomarker	[14]
Breast cancer	DIS7DPX1	Limited	Biomarker	[15]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[15]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Altered Expression	[16]
Cocaine addiction	DISHTRXG	Limited	Biomarker	[17]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[16]
Liver cancer	DISDE4BI	Limited	Altered Expression	[16]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[18]
Neoplasm	DISZKGEW	Limited	Biomarker	[16]
Nervous system disease	DISJ7GGT	Limited	Biomarker	[2]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[19]
Schizophrenia	DISSRV2N	Limited	Biomarker	[2]

1 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 Neuronal calcium sensor 1 (NCS1).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Neuronal calcium sensor 1 (NCS1).	[21]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Neuronal calcium sensor 1 (NCS1).	[22]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Neuronal calcium sensor 1 (NCS1).	[23]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Neuronal calcium sensor 1 (NCS1).	[24]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Neuronal calcium sensor 1 (NCS1).	[25]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Neuronal calcium sensor 1 (NCS1).	[26]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Neuronal calcium sensor 1 (NCS1).	[27]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Neuronal calcium sensor 1 (NCS1).	[28]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Neuronal calcium sensor 1 (NCS1).	[29]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Neuronal calcium sensor 1 (NCS1).	[30]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Neuronal calcium sensor 1 (NCS1).	[31]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Neuronal calcium sensor 1 (NCS1).	[32]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Neuronal calcium sensor 1 (NCS1).	[33]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Neuronal calcium sensor 1 (NCS1).	[34]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Neuronal calcium sensor 1 (NCS1).	[35]

References

• [1] The Complex Conformational Dynamics of Neuronal Calcium Sensor-1: A Single Molecule Perspective.Front Mol Neurosci. 2018 Dec 17;11:468. doi: 10.3389/fnmol.2018.00468. eCollection 2018.
• [2] Current Understanding of the Role of Neuronal Calcium Sensor 1 in Neurological Disorders.Mol Neurobiol. 2019 Sep;56(9):6080-6094. doi: 10.1007/s12035-019-1497-2. Epub 2019 Feb 4.
• [3] ER-mitochondria cross-talk is regulated by the Ca(2+) sensor NCS1 and is impaired in Wolfram syndrome.Sci Signal. 2018 Oct 23;11(553):eaaq1380. doi: 10.1126/scisignal.aaq1380.
• [4] IL1 receptor accessory protein like, a protein involved in X-linked mental retardation, interacts with Neuronal Calcium Sensor-1 and regulates exocytosis.Hum Mol Genet. 2003 Jun 15;12(12):1415-25. doi: 10.1093/hmg/ddg147.
• [5] Genome-wide association study of the rate of cognitive decline in Alzheimer's disease.Alzheimers Dement. 2014 Jan;10(1):45-52. doi: 10.1016/j.jalz.2013.01.008. Epub 2013 Mar 25.
• [6] Electroacupuncture Alleviates Brain Damage Through Targeting of Neuronal Calcium Sensor 1 by miR-191a-5p After Ischemic Stroke.Rejuvenation Res. 2017 Dec;20(6):492-505. doi: 10.1089/rej.2017.1920. Epub 2017 Jul 17.
• [7] Mice lacking neuronal calcium sensor-1 show social and cognitive deficits.Behav Brain Res. 2020 Mar 2;381:112420. doi: 10.1016/j.bbr.2019.112420. Epub 2019 Dec 9.
• [8] Incident Chronic Spinal Pain and Depressive Disorders: Data From the National Comorbidity Survey.J Pain. 2019 Apr;20(4):481-488. doi: 10.1016/j.jpain.2018.11.002. Epub 2018 Nov 22.
• [9] Deciphering the Inhibition of the Neuronal Calcium Sensor 1 and the Guanine Exchange Factor Ric8a with a Small Phenothiazine Molecule for the Rational Generation of Therapeutic Synapse Function Regulators.J Med Chem. 2018 Jul 26;61(14):5910-5921. doi: 10.1021/acs.jmedchem.8b00088. Epub 2018 Jul 17.
• [10] Involvement of dual-strand of the miR-144 duplex and their targets in the pathogenesis of lung squamous cell carcinoma.Cancer Sci. 2019 Jan;110(1):420-432. doi: 10.1111/cas.13853. Epub 2018 Dec 6.
• [11] NCS-1 Deficiency Is Associated With Obesity and Diabetes Type 2 in Mice.Front Mol Neurosci. 2019 Apr 3;12:78. doi: 10.3389/fnmol.2019.00078. eCollection 2019.
• [12] NCS-1 is a regulator of calcium signaling in health and disease.Biochim Biophys Acta Mol Cell Res. 2018 Nov;1865(11 Pt B):1660-1667. doi: 10.1016/j.bbamcr.2018.05.005. Epub 2018 May 8.
• [13] When Emotional Pain Becomes Physical: Adverse Childhood Experiences, Pain, and the Role of Mood and Anxiety Disorders.J Clin Psychol. 2017 Oct;73(10):1403-1428. doi: 10.1002/jclp.22444. Epub 2017 Mar 22.
• [14] Emerging Roles of Neuronal Ca(2+) Sensor-1 in Cardiac and Neuronal Tissues: A Mini Review.Front Mol Neurosci. 2019 Mar 4;12:56. doi: 10.3389/fnmol.2019.00056. eCollection 2019.
• [15] NCS-1 expression is higher in basal breast cancers and regulates calcium influx and cytotoxic responses to doxorubicin.Mol Oncol. 2020 Jan;14(1):87-104. doi: 10.1002/1878-0261.12589. Epub 2019 Nov 11.
• [16] Hepatocellular Carcinoma Outcome Is Predicted by Expression of Neuronal Calcium Sensor 1.Cancer Epidemiol Biomarkers Prev. 2018 Sep;27(9):1091-1100. doi: 10.1158/1055-9965.EPI-18-0167. Epub 2018 May 22.
• [17] Neuronal calcium sensor-1 and cocaine addiction: a genetic association study in African-Americans and European Americans.Neurosci Lett. 2012 Nov 30;531(1):46-51. doi: 10.1016/j.neulet.2012.09.014. Epub 2012 Sep 20.
• [18] Neuronal calcium sensor 1 (NCS1) promotes motility and metastatic spread of breast cancer cells in vitro and in vivo.FASEB J. 2019 Apr;33(4):4802-4813. doi: 10.1096/fj.201802004R. Epub 2018 Dec 28.
• [19] Inhibition of paclitaxel-induced decreases in calcium signaling.J Biol Chem. 2012 Nov 2;287(45):37907-16. doi: 10.1074/jbc.M112.385070. Epub 2012 Sep 17.
• [20] 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.
• [21] 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.
• [22] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [23] 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.
• [24] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [25] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [26] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [27] 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.
• [28] 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.
• [29] 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.
• [30] Gene induction and apoptosis in human hepatocellular carci-noma cells SMMC-7721 exposed to 5-aza-2'-deoxycytidine. Chin Med J (Engl). 2007 Sep 20;120(18):1626-31.
• [31] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [32] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [33] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [34] 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.
• [35] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.