Details of Drug Off-Target (DOT)

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

• DOT Name: Calcium-activated potassium channel subunit beta-2 (KCNMB2)
• Synonyms: BK channel subunit beta-2; BKbeta2; Hbeta2; Calcium-activated potassium channel, subfamily M subunit beta-2; Charybdotoxin receptor subunit beta-2; Hbeta3; K(VCA)beta-2; Maxi K channel subunit beta-2; Slo-beta-2
• Gene Name: KCNMB2
• Related Disease:
  Alzheimer disease
  Major depressive disorder
  Triple negative breast cancer
  Bipolar disorder
  Psychotic disorder
  Schizophrenia
  Amyotrophic lateral sclerosis type 1
  Glanzmann thrombasthenia
  Mental disorder
• UniProt ID: KCMB2_HUMAN
• PDB ID: 1JO6
• Pfam ID: PF03185 ; PF09303
• Sequence:
  MFIWTSGRTSSSYRHDEKRNIYQKIRDHDLLDKRKTVTALKAGEDRAILLGLAMMVCSIM
  MYFLLGITLLRSYMQSVWTEESQCTLLNASITETFNCSFSCGPDCWKLSQYPCLQVYVNL
  TSSGEKLLLYHTEETIKINQKCSYIPKCGKNFEESMSLVNVVMENFRKYQHFSCYSDPEG
  NQKSVILTKLYSSNVLFHSLFWPTCMMAGGVAIVAMVKLTQYLSLLCERIQRINR
• 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. Acts as a negative regulator that confers rapid and complete inactivation of KCNMA1 channel complex. May participate in KCNMA1 inactivation in chromaffin cells of the adrenal gland or in hippocampal CA1 neurons.
• Tissue Specificity: Expressed in kidney, heart and brain. Highly expressed in ovary. Expressed at low level 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

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[1]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[2]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[3]
Bipolar disorder	DISAM7J2	moderate	Genetic Variation	[4]
Psychotic disorder	DIS4UQOT	moderate	Genetic Variation	[4]
Schizophrenia	DISSRV2N	moderate	Genetic Variation	[4]
Amyotrophic lateral sclerosis type 1	DIS5A2M0	Limited	Genetic Variation	[5]
Glanzmann thrombasthenia	DISFGGTG	Limited	Genetic Variation	[6]
Mental disorder	DIS3J5R8	Limited	Genetic Variation	[4]

3 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-2 (KCNMB2).	[7]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Calcium-activated potassium channel subunit beta-2 (KCNMB2).	[9]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Calcium-activated potassium channel subunit beta-2 (KCNMB2).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Calcium-activated potassium channel subunit beta-2 (KCNMB2).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Calcium-activated potassium channel subunit beta-2 (KCNMB2).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Calcium-activated potassium channel subunit beta-2 (KCNMB2).	[12]

References

• [1] CSF protein changes associated with hippocampal sclerosis risk gene variants highlight impact of GRN/PGRN.Exp Gerontol. 2017 Apr;90:83-89. doi: 10.1016/j.exger.2017.01.025. Epub 2017 Feb 9.
• [2] Genome-wide meta-analyses of stratified depression in Generation Scotland and UK Biobank.Transl Psychiatry. 2018 Jan 10;8(1):9. doi: 10.1038/s41398-017-0034-1.
• [3] Integration of whole-genome sequencing and functional screening identifies a prognostic signature for lung metastasis in triple-negative breast cancer.Int J Cancer. 2019 Nov 15;145(10):2850-2860. doi: 10.1002/ijc.32329. Epub 2019 Apr 29.
• [4] Genome-wide association study in a Swedish population yields support for greater CNV and MHC involvement in schizophrenia compared with bipolar disorder.Mol Psychiatry. 2012 Sep;17(9):880-6. doi: 10.1038/mp.2012.73. Epub 2012 Jun 12.
• [5] Genome-wide association study combining pathway analysis for typical sporadic amyotrophic lateral sclerosis in Chinese Han populations.Neurobiol Aging. 2014 Jul;35(7):1778.e9-1778.e23. doi: 10.1016/j.neurobiolaging.2014.01.014. Epub 2014 Jan 17.
• [6] 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.
• [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] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [9] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [10] Gene-expression profiling during curcumin-induced apoptosis reveals downregulation of CXCR4. Exp Hematol. 2007 Jan;35(1):84-95.
• [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] 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.