Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTE70DMK)

• DOT Name: Voltage-dependent calcium channel gamma-4 subunit (CACNG4)
• Synonyms: Neuronal voltage-gated calcium channel gamma-4 subunit; Transmembrane AMPAR regulatory protein gamma-4; TARP gamma-4
• Gene Name: CACNG4
• Related Disease:
  Acute myocardial infarction
  Plasma cell myeloma
  Schizophrenia
• UniProt ID: CCG4_HUMAN
• Pfam ID: PF00822
• Sequence:
  MVRCDRGLQMLLTTAGAFAAFSLMAIAIGTDYWLYSSAHICNGTNLTMDDGPPPRRARGD
  LTHSGLWRVCCIEGIYKGHCFRINHFPEDNDYDHDSSEYLLRIVRASSVFPILSTILLLL
  GGLCIGAGRIYSRKNNIVLSAGILFVAAGLSNIIGIIVYISSNTGDPSDKRDEDKKNHYN
  YGWSFYFGALSFIVAETVGVLAVNIYIEKNKELRFKTKREFLKASSSSPYARMPSYRYRR
  RRSRSSSRSTEASPSRDVSPMGLKITGAIPMGELSMYTLSREPLKVTTAASYSPDQEASF
  LQVHDFFQQDLKEGFHVSMLNRRTTPV
• Function: Regulates the activity of L-type calcium channels that contain CACNA1C as pore-forming subunit. Regulates the trafficking and gating properties of AMPA-selective glutamate receptors (AMPARs), including GRIA1 and GRIA4. Promotes their targeting to the cell membrane and synapses and modulates their gating properties by slowing their rates of activation, deactivation and desensitization and by mediating their resensitization.
• Tissue Specificity: Detected in heart left ventricle.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Cardiac muscle contraction (hsa04260)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  Oxytocin sig.ling pathway (hsa04921)
  Hypertrophic cardiomyopathy (hsa05410)
  Arrhythmogenic right ventricular cardiomyopathy (hsa05412)
  Dilated cardiomyopathy (hsa05414)
• Reactome Pathway:
  Trafficking of AMPA receptors (R-HSA-399719)
  Phase 0 - rapid depolarisation (R-HSA-5576892)
  Phase 2 - plateau phase (R-HSA-5576893)
  LGI-ADAM interactions (R-HSA-5682910)
  Presynaptic depolarization and calcium channel opening (R-HSA-112308)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myocardial infarction	DISE3HTG	Strong	Altered Expression	[1]
Plasma cell myeloma	DIS0DFZ0	Strong	Genetic Variation	[2]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[3]

2 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 Voltage-dependent calcium channel gamma-4 subunit (CACNG4).	[4]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Voltage-dependent calcium channel gamma-4 subunit (CACNG4).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Voltage-dependent calcium channel gamma-4 subunit (CACNG4).	[5]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Voltage-dependent calcium channel gamma-4 subunit (CACNG4).	[6]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Voltage-dependent calcium channel gamma-4 subunit (CACNG4).	[7]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Voltage-dependent calcium channel gamma-4 subunit (CACNG4).	[6]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Voltage-dependent calcium channel gamma-4 subunit (CACNG4).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Voltage-dependent calcium channel gamma-4 subunit (CACNG4).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Voltage-dependent calcium channel gamma-4 subunit (CACNG4).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Voltage-dependent calcium channel gamma-4 subunit (CACNG4).	[11]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Voltage-dependent calcium channel gamma-4 subunit (CACNG4).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Voltage-dependent calcium channel gamma-4 subunit (CACNG4).	[14]

References

• [1] Identification of Transcription Factor-Gene Regulatory Network in Acute Myocardial Infarction.Heart Lung Circ. 2017 Apr;26(4):343-353. doi: 10.1016/j.hlc.2016.06.1209. Epub 2016 Jul 26.
• [2] Host genetic susceptibility to Clostridium difficile infections in patients undergoing autologous stem cell transplantation: a genome-wide association study.Support Care Cancer. 2018 Sep;26(9):3127-3134. doi: 10.1007/s00520-018-4173-6. Epub 2018 Mar 28.
• [3] Evaluation of voltage-dependent calcium channel gene families identified several novel potential susceptible genes to schizophrenia.Sci Rep. 2016 Apr 22;6:24914. doi: 10.1038/srep24914.
• [4] 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.
• [5] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [6] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [7] 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.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [10] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [11] 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.
• [12] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [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] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.