Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2SRKQE)

• DOT Name: Calcium-activated potassium channel subunit beta-3 (KCNMB3)
• Synonyms: BK channel subunit beta-3; BKbeta3; Hbeta3; Calcium-activated potassium channel, subfamily M subunit beta-3; Charybdotoxin receptor subunit beta-3; K(VCA)beta-3; Maxi K channel subunit beta-3; Slo-beta-3
• Gene Name: KCNMB3
• Related Disease:
  Epilepsy, idiopathic generalized
  Neuralgia
  Squamous cell carcinoma
  Glanzmann thrombasthenia
• UniProt ID: KCMB3_HUMAN
• Pfam ID: PF03185
• Sequence:
  MDFSPSSELGFHFVAFILLTRHRTAFPASGKKRETDYSDGDPLDVHKRLPSSAGEDRAVM
  LGFAMMGFSVLMFFLLGTTILKPFMLSIQREESTCTAIHTDIMDDWLDCAFTCGVHCHGQ
  GKYPCLQVFVNLSHPGQKALLHYNEEAVQINPKCFYTPKCHQDRNDLLNSALDIKEFFDH
  KNGTPFSCFYSPASQSEDVILIKKYDQMAIFHCLFWPSLTLLGGALIVGMVRLTQHLSLL
  CEKYSTVVRDEVGGKVPYIEQHQFKLCIMRRSKGRAEKS
• 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. Alters the functional properties of the current expressed by the KCNMA1 channel. Isoform 2, isoform 3 and isoform 4 partially inactivate the current of KCNBMA. Isoform 4 induces a fast and incomplete inactivation of KCNMA1 channel that is detectable only at large depolarizations. In contrast, isoform 1 does not induce detectable inactivation of KCNMA1. Two or more subunits of KCNMB3 are required to block the KCNMA1 tetramer.
• Tissue Specificity: Isoform 1, isoform 3 and isoform 4 are widely expressed. Isoform 2 is expressed placenta, pancreas, kidney and heart. Isoform 1 and isoform 3 are highly expressed in pancreas and testis.
• 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

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epilepsy, idiopathic generalized	DISODZC9	Strong	Genetic Variation	[1]
Neuralgia	DISWO58J	Strong	Biomarker	[2]
Squamous cell carcinoma	DISQVIFL	moderate	Biomarker	[3]
Glanzmann thrombasthenia	DISFGGTG	Limited	Genetic Variation	[4]

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 Calcium-activated potassium channel subunit beta-3 (KCNMB3).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Calcium-activated potassium channel subunit beta-3 (KCNMB3).	[8]

4 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 Calcium-activated potassium channel subunit beta-3 (KCNMB3).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Calcium-activated potassium channel subunit beta-3 (KCNMB3).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Calcium-activated potassium channel subunit beta-3 (KCNMB3).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Calcium-activated potassium channel subunit beta-3 (KCNMB3).	[10]

References

• [1] Allelic association of a truncation mutation of the KCNMB3 gene with idiopathic generalized epilepsy.Am J Med Genet B Neuropsychiatr Genet. 2007 Jan 5;144B(1):10-3. doi: 10.1002/ajmg.b.30369.
• [2] KCNMB3 in spinal microglia contributes to the generation and maintenance of neuropathic pain in mice.Int J Mol Med. 2019 Oct;44(4):1585-1593. doi: 10.3892/ijmm.2019.4279. Epub 2019 Jul 19.
• [3] Identification of novel candidate target genes, including EPHB3, MASP1 and SST at 3q26.2-q29 in squamous cell carcinoma of the lung.BMC Cancer. 2009 Jul 16;9:237. doi: 10.1186/1471-2407-9-237.
• [4] Critical role of beta3 integrin in experimental postmenopausal osteoporosis.J Bone Miner Res. 2005 Dec;20(12):2116-23. doi: 10.1359/JBMR.050724. Epub 2005 Jul 25.
• [5] 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.
• [6] 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.
• [7] Inorganic arsenic exposure promotes malignant progression by HDAC6-mediated down-regulation of HTRA1. J Appl Toxicol. 2023 Aug;43(8):1214-1224. doi: 10.1002/jat.4457. Epub 2023 Mar 11.
• [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] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [10] 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.