Details of Drug Off-Target (DOT)

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

• DOT Name: Cerebellin-1 (CBLN1)
• Synonyms: Precerebellin) -cerebellin]
• Gene Name: CBLN1
• Related Disease: Cerebellar ataxia
• UniProt ID: CBLN1_HUMAN
• PDB ID: 5KC5; 5KC6; 5KC7; 5KCA
• Pfam ID: PF00386
• Sequence:
  MLGVLELLLLGAAWLAGPARGQNETEPIVLEGKCLVVCDSNPTSDPTGTALGISVRSGSA
  KVAFSAIRSTNHEPSEMSNRTMIIYFDQVLVNIGNNFDSERSTFIAPRKGIYSFNFHVVK
  VYNRQTIQVSLMLNGWPVISAFAGDQDVTREAASNGVLIQMEKGDRAYLKLERGNLMGGW
  KYSTFSGFLVFPL
• Function: Required for synapse integrity and synaptic plasticity. During cerebellar synapse formation, essential for the matching and maintenance of pre- and post-synaptic elements at parallel fiber-Purkinje cell synapses, the establishment of the proper pattern of climbing fiber-Purkinje cell innervation, and induction of long-term depression at parallel fiber-Purkinje cell synapses. Plays a role as a synaptic organizer that acts bidirectionally on both pre- and post-synaptic components. On the one hand induces accumulation of synaptic vesicles in the pre-synaptic part by binding with NRXN1 and in other hand induces clustering of GRID2 and its associated proteins at the post-synaptic site through association of GRID2. NRXN1-CBLN1-GRID2 complex directly induces parallel fiber protrusions that encapsulate spines of Purkinje cells leading to accumulation of GRID2 and synaptic vesicles. Required for CBLN3 export from the endoplasmic reticulum and secretion. NRXN1-CBLN1-GRID2 complex mediates the D-Serine-dependent long term depression signals and AMPA receptor endocytosis. Essential for long-term maintenance but not establishment of excitatory synapses. Inhibits the formation and function of inhibitory GABAergic synapses in cerebellar Purkinje cells; The cerebellin peptide exerts neuromodulatory functions. Directly stimulates norepinephrine release via the adenylate cyclase/PKA-dependent signaling pathway; and indirectly enhances adrenocortical secretion in vivo, through a paracrine mechanism involving medullary catecholamine release.
• Tissue Specificity: In the Purkinje cells postsynaptic structures. In the cerebellum, cerebellin is much less abundant than [des-Ser1]-cerebellin.

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cerebellar ataxia	DIS9IRAV	Strong	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Cerebellin-1 (CBLN1).	[2]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Cerebellin-1 (CBLN1).	[3]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Cerebellin-1 (CBLN1).	[4]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Cerebellin-1 (CBLN1).	[5]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Cerebellin-1 (CBLN1).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Cerebellin-1 (CBLN1).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Cerebellin-1 (CBLN1).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Cerebellin-1 (CBLN1).	[11]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Cerebellin-1 (CBLN1).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Cerebellin-1 (CBLN1).	[8]

References

• [1] Glycosylation of Cblns attenuates their receptor binding.Brain Res. 2018 Sep 1;1694:129-139. doi: 10.1016/j.brainres.2018.05.022. Epub 2018 May 18.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Comparative Analysis of Transcriptomic Changes including mRNA and microRNA Expression Induced by the Xenoestrogens Zearalenone and Bisphenol A in Human Ovarian Cells. Toxins (Basel). 2023 Feb 9;15(2):140. doi: 10.3390/toxins15020140.
• [4] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] 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.