Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYQG46B)

• DOT Name: Calcium-activated potassium channel subunit beta-4 (KCNMB4)
• Synonyms: BK channel subunit beta-4; BKbeta4; Hbeta4; Calcium-activated potassium channel, subfamily M subunit beta-4; Charybdotoxin receptor subunit beta-4; K(VCA)beta-4; Maxi K channel subunit beta-4; Slo-beta-4
• Gene Name: KCNMB4
• UniProt ID: KCMB4_HUMAN
• PDB ID: 5Y7L; 6V22; 6V35
• Pfam ID: PF03185
• Sequence:
  MAKLRVAYEYTEAEDKSIRLGLFLIISGVVSLFIFGFCWLSPALQDLQATEANCTVLSVQ
  QIGEVFECTFTCGADCRGTSQYPCVQVYVNNSESNSRALLHSDEHQLLTNPKCSYIPPCK
  RENQKNLESVMNWQQYWKDEIGSQPFTCYFNQHQRPDDVLLHRTHDEIVLLHCFLWPLVT
  FVVGVLIVVLTICAKSLAVKAEAMKKRKFS
• Function: Regulatory subunit of the calcium activated potassium KCNMA1 (maxiK) channel. Modulates the calcium sensitivity and gating kinetics of KCNMA1, thereby contributing to KCNMA1 channel diversity. Decreases the gating kinetics and calcium sensitivity of the KCNMA1 channel, but with fast deactivation kinetics. May decrease KCNMA1 channel openings at low calcium concentrations but increases channel openings at high calcium concentrations. Makes KCNMA1 channel resistant to 100 nM charybdotoxin (CTX) toxin concentrations.
• Tissue Specificity: Predominantly expressed in brain. In brain, it is expressed in the cerebellum, cerebral cortex, medulla, spinal cord, occipital pole, frontal lobe, temporal lobe, putamen, amygdala, caudate nucleus, corpus callosum, hippocampus, substantia nigra and thalamus. Weakly or not expressed in other tissues.
• KEGG Pathway:
  cGMP-PKG sig.ling pathway (hsa04022)
  Vascular smooth muscle contraction (hsa04270)
  Insulin secretion (hsa04911)
• Reactome Pathway:
  cGMP effects (R-HSA-418457)
  Ca2+ activated K+ channels (R-HSA-1296052)

Molecular Interaction Atlas (MIA) of This DOT

13 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 Calcium-activated potassium channel subunit beta-4 (KCNMB4).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Calcium-activated potassium channel subunit beta-4 (KCNMB4).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Calcium-activated potassium channel subunit beta-4 (KCNMB4).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Calcium-activated potassium channel subunit beta-4 (KCNMB4).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Calcium-activated potassium channel subunit beta-4 (KCNMB4).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Calcium-activated potassium channel subunit beta-4 (KCNMB4).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Calcium-activated potassium channel subunit beta-4 (KCNMB4).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Calcium-activated potassium channel subunit beta-4 (KCNMB4).	[8]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Calcium-activated potassium channel subunit beta-4 (KCNMB4).	[8]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Calcium-activated potassium channel subunit beta-4 (KCNMB4).	[9]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Calcium-activated potassium channel subunit beta-4 (KCNMB4).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Calcium-activated potassium channel subunit beta-4 (KCNMB4).	[12]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Calcium-activated potassium channel subunit beta-4 (KCNMB4).	[13]

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 increases the methylation of Calcium-activated potassium channel subunit beta-4 (KCNMB4).	[11]

References

• [1] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [2] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [3] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 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.
• [8] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [9] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] 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.
• [12] 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.
• [13] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.