Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTO4KNJ4)

• DOT Name: Calcium-activated potassium channel subunit beta-1 (KCNMB1)
• Synonyms: BK channel subunit beta-1; BKbeta; BKbeta1; Hbeta1; Calcium-activated potassium channel, subfamily M subunit beta-1; Calcium-activated potassium channel subunit beta; Charybdotoxin receptor subunit beta-1; K(VCA)beta-1; Maxi K channel subunit beta-1; Slo-beta-1; Slo-beta
• Gene Name: KCNMB1
• Related Disease:
  Arteriosclerosis
  Asthma
  Atherosclerosis
  Bacteremia
  Chronic kidney disease
  High blood pressure
  Kidney failure
  Non-insulin dependent diabetes
  Obstructive lung disease
  Obstructive sleep apnea
  Pulmonary fibrosis
  Essential hypertension
  Glioma
• UniProt ID: KCMB1_HUMAN
• Pfam ID: PF03185
• Sequence:
  MVKKLVMAQKRGETRALCLGVTMVVCAVITYYILVTTVLPLYQKSVWTQESKCHLIETNI
  RDQEELKGKKVPQYPCLWVNVSAAGRWAVLYHTEDTRDQNQQCSYIPGSVDNYQTARADV
  EKVRAKFQEQQVFYCFSAPRGNETSVLFQRLYGPQALLFSLFWPTFLLTGGLLIIAMVKS
  NQYLSILAAQK
• 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. Increases the apparent Ca(2+)/voltage sensitivity of the KCNMA1 channel. It also modifies KCNMA1 channel kinetics and alters its pharmacological properties. It slows down the activation and the deactivation kinetics of the channel. Acts as a negative regulator of smooth muscle contraction by enhancing the calcium sensitivity to KCNMA1. Its presence is also a requirement for internal binding of the KCNMA1 channel opener dehydrosoyasaponin I (DHS-1) triterpene glycoside and for external binding of the agonist hormone 17-beta-estradiol (E2). Increases the binding activity of charybdotoxin (CTX) toxin to KCNMA1 peptide blocker by increasing the CTX association rate and decreasing the dissociation rate.
• Tissue Specificity: Abundantly expressed in smooth muscle. Low levels of expression in most other tissues. Within the brain, relatively high levels found in hippocampus and corpus callosum.
• KEGG Pathway:
  cGMP-PKG sig.ling pathway (hsa04022)
  Vascular smooth muscle contraction (hsa04270)
  Insulin secretion (hsa04911)
• Reactome Pathway:
  cGMP effects (R-HSA-418457)
  Sensory processing of sound by inner hair cells of the cochlea (R-HSA-9662360)
  Acetylcholine inhibits contraction of outer hair cells (R-HSA-9667769)
  Ca2+ activated K+ channels (R-HSA-1296052)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[1]
Asthma	DISW9QNS	Strong	Genetic Variation	[2]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[1]
Bacteremia	DIS6N9RZ	Strong	Biomarker	[3]
Chronic kidney disease	DISW82R7	Strong	Genetic Variation	[4]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[4]
Kidney failure	DISOVQ9P	Strong	Genetic Variation	[4]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[5]
Obstructive lung disease	DIS4IIDZ	Strong	Genetic Variation	[2]
Obstructive sleep apnea	DIS0SVD1	Strong	Biomarker	[6]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[7]
Essential hypertension	DIS7WI98	Limited	Genetic Variation	[8]
Glioma	DIS5RPEH	Limited	Altered Expression	[9]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Verapamil	DMA7PEW	Phase 2/3 Trial	Calcium-activated potassium channel subunit beta-1 (KCNMB1) affects the response to substance of Verapamil.	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Calcium-activated potassium channel subunit beta-1 (KCNMB1).	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Calcium-activated potassium channel subunit beta-1 (KCNMB1).	[11]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Calcium-activated potassium channel subunit beta-1 (KCNMB1).	[12]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Calcium-activated potassium channel subunit beta-1 (KCNMB1).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Calcium-activated potassium channel subunit beta-1 (KCNMB1).	[14]
	DM9CEI5		increases the activity of Calcium-activated potassium channel subunit beta-1 (KCNMB1).	[15]

References

• [1] 7-Ketocholesterol induces the reduction of KCNMB1 in atherosclerotic blood vessels.Biochem Biophys Res Commun. 2015 Feb 13;457(3):324-7. doi: 10.1016/j.bbrc.2014.12.109. Epub 2015 Jan 7.
• [2] An african-specific functional polymorphism in KCNMB1 shows sex-specific association with asthma severity.Hum Mol Genet. 2008 Sep 1;17(17):2681-90. doi: 10.1093/hmg/ddn168. Epub 2008 Jun 4.
• [3] Group A Streptococcus Induces LAPosomes via SLO/1 Integrin/NOX2/ROS Pathway in Endothelial Cells That Are Ineffective in Bacterial Killing and Suppress Xenophagy.mBio. 2019 Oct 1;10(5):e02148-19. doi: 10.1128/mBio.02148-19.
• [4] Common charge-shift mutation Glu65Lys in K+ channel ?Subunit KCNMB1: pleiotropic consequences for glomerular filtration rate and progressive renal disease.Am J Nephrol. 2010;32(5):414-24. doi: 10.1159/000320131. Epub 2010 Sep 23.
• [5] Impaired Ca2+-dependent activation of large-conductance Ca2+-activated K+ channels in the coronary artery smooth muscle cells of Zucker Diabetic Fatty rats.Biophys J. 2008 Dec;95(11):5165-77. doi: 10.1529/biophysj.108.138339. Epub 2008 Sep 12.
• [6] Maxi-K+ channel beta1 expression in sleep apnea patients and its modulation by CPAP treatment.Am J Hypertens. 2009 Feb;22(2):197-202. doi: 10.1038/ajh.2008.342. Epub 2008 Dec 4.
• [7] The Role of KCNMB1 and BK Channels in Myofibroblast Differentiation and Pulmonary Fibrosis.Am J Respir Cell Mol Biol. 2020 Feb;62(2):191-203. doi: 10.1165/rcmb.2019-0163OC.
• [8] The dominant models of KCNJ11 E23K and KCNMB1 E65K are associated with essential hypertension (EH) in Asian: Evidence from a meta-analysis.Medicine (Baltimore). 2019 Jun;98(23):e15828. doi: 10.1097/MD.0000000000015828.
• [9] Current transients associated with BK channels in human glioma cells.J Membr Biol. 2003 Jun 1;193(3):201-13. doi: 10.1007/s00232-003-2019-7.
• [10] 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.
• [11] Identification of transcriptional biomarkers induced by SERMS in human endometrial cells using multivariate analysis of DNA microarrays. Biomarkers. 2004 Nov-Dec;9(6):447-60.
• [12] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [14] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.
• [15] Calcium- and voltage-gated potassium (BK) channel activators in the 5-cholanic acid-3-ol analogue series with modifications in the lateral chain. ChemMedChem. 2012 Oct;7(10):1784-92. doi: 10.1002/cmdc.201200290. Epub 2012 Sep 4.
• [16] KCNMB1 genotype influences response to verapamil SR and adverse outcomes in the INternational VErapamil SR/Trandolapril STudy (INVEST). Pharmacogenet Genomics. 2007 Sep;17(9):719-29. doi: 10.1097/FPC.0b013e32810f2e3c.