Details of Drug Off-Target (DOT)

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

• DOT Name: Calcium-activated potassium channel subunit alpha-1 (KCNMA1)
• Synonyms: BK channel; BKCA alpha; Calcium-activated potassium channel, subfamily M subunit alpha-1; K(VCA)alpha; KCa1.1; Maxi K channel; MaxiK; Slo-alpha; Slo1; Slowpoke homolog; Slo homolog; hSlo
• Gene Name: KCNMA1
• Related Disease:
  Generalized epilepsy-paroxysmal dyskinesia syndrome
  Liang-Wang syndrome
• UniProt ID: KCMA1_HUMAN
• PDB ID: 2K44; 3MT5; 3NAF; 6ND0; 6V22; 6V35; 6V38; 6V3G; 6V5A; 8GH9; 8GHF; 8GHG
• Pfam ID: PF03493 ; PF00520 ; PF21014
• Sequence:
  MANGGGGGGGSSGGGGGGGGSSLRMSSNIHANHLSLDASSSSSSSSSSSSSSSSSSSSSS
  VHEPKMDALIIPVTMEVPCDSRGQRMWWAFLASSMVTFFGGLFIILLWRTLKYLWTVCCH
  CGGKTKEAQKINNGSSQADGTLKPVDEKEEAVAAEVGWMTSVKDWAGVMISAQTLTGRVL
  VVLVFALSIGALVIYFIDSSNPIESCQNFYKDFTLQIDMAFNVFFLLYFGLRFIAANDKL
  WFWLEVNSVVDFFTVPPVFVSVYLNRSWLGLRFLRALRLIQFSEILQFLNILKTSNSIKL
  VNLLSIFISTWLTAAGFIHLVENSGDPWENFQNNQALTYWECVYLLMVTMSTVGYGDVYA
  KTTLGRLFMVFFILGGLAMFASYVPEIIELIGNRKKYGGSYSAVSGRKHIVVCGHITLES
  VSNFLKDFLHKDRDDVNVEIVFLHNISPNLELEALFKRHFTQVEFYQGSVLNPHDLARVK
  IESADACLILANKYCADPDAEDASNIMRVISIKNYHPKIRIITQMLQYHNKAHLLNIPSW
  NWKEGDDAICLAELKLGFIAQSCLAQGLSTMLANLFSMRSFIKIEEDTWQKYYLEGVSNE
  MYTEYLSSAFVGLSFPTVCELCFVKLKLLMIAIEYKSANRESRILINPGNHLKIQEGTLG
  FFIASDAKEVKRAFFYCKACHDDITDPKRIKKCGCKRPKMSIYKRMRRACCFDCGRSERD
  CSCMSGRVRGNVDTLERAFPLSSVSVNDCSTSFRAFEDEQPSTLSPKKKQRNGGMRNSPN
  TSPKLMRHDPLLIPGNDQIDNMDSNVKKYDSTGMFHWCAPKEIEKVILTRSEAAMTVLSG
  HVVVCIFGDVSSALIGLRNLVMPLRASNFHYHELKHIVFVGSIEYLKREWETLHNFPKVS
  ILPGTPLSRADLRAVNINLCDMCVILSANQNNIDDTSLQDKECILASLNIKSMQFDDSIG
  VLQANSQGFTPPGMDRSSPDNSPVHGMLRQPSITTGVNIPIITELVNDTNVQFLDQDDDD
  DPDTELYLTQPFACGTAFAVSVLDSLMSATYFNDNILTLIRTLVTGGATPELEALIAEEN
  ALRGGYSTPQTLANRDRCRVAQLALLDGPFADLGDGGCYGDLFCKALKTYNMLCFGIYRL
  RDAHLSTPSQCTKRYVITNPPYEFELVPTDLIFCLMQFDHNAGQSRASLSHSSHSSQSSS
  KKSSSVHSIPSTANRQNRPKSRESRDKQKYVQEERL
• Function: Potassium channel activated by both membrane depolarization or increase in cytosolic Ca(2+) that mediates export of K(+). It is also activated by the concentration of cytosolic Mg(2+). Its activation dampens the excitatory events that elevate the cytosolic Ca(2+) concentration and/or depolarize the cell membrane. It therefore contributes to repolarization of the membrane potential. Plays a key role in controlling excitability in a number of systems, such as regulation of the contraction of smooth muscle, the tuning of hair cells in the cochlea, regulation of transmitter release, and innate immunity. In smooth muscles, its activation by high level of Ca(2+), caused by ryanodine receptors in the sarcoplasmic reticulum, regulates the membrane potential. In cochlea cells, its number and kinetic properties partly determine the characteristic frequency of each hair cell and thereby helps to establish a tonotopic map. Kinetics of KCNMA1 channels are determined by alternative splicing, phosphorylation status and its combination with modulating beta subunits. Highly sensitive to both iberiotoxin (IbTx) and charybdotoxin (CTX).
• Tissue Specificity: Widely expressed. Except in myocytes, it is almost ubiquitously expressed.
• KEGG Pathway:
  cGMP-PKG sig.ling pathway (hsa04022)
  Vascular smooth muscle contraction (hsa04270)
  Insulin secretion (hsa04911)
  Renin secretion (hsa04924)
  Salivary secretion (hsa04970)
  Pancreatic secretion (hsa04972)
• 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

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Generalized epilepsy-paroxysmal dyskinesia syndrome	DIS5Z2SW	Definitive	Autosomal dominant	[1]
Liang-Wang syndrome	DISMMMZL	Limited	Autosomal dominant	[2]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	Calcium-activated potassium channel subunit alpha-1 (KCNMA1) affects the response to substance of Paclitaxel.	[19]
Topotecan	DMP6G8T	Approved	Calcium-activated potassium channel subunit alpha-1 (KCNMA1) affects the response to substance of Topotecan.	[19]
	DM9CEI5		Calcium-activated potassium channel subunit alpha-1 (KCNMA1) increases the response to substance of .	[20]

13 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 alpha-1 (KCNMA1).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Calcium-activated potassium channel subunit alpha-1 (KCNMA1).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the activity of Calcium-activated potassium channel subunit alpha-1 (KCNMA1).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Calcium-activated potassium channel subunit alpha-1 (KCNMA1).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Calcium-activated potassium channel subunit alpha-1 (KCNMA1).	[8]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Calcium-activated potassium channel subunit alpha-1 (KCNMA1).	[9]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Calcium-activated potassium channel subunit alpha-1 (KCNMA1).	[10]
Malathion	DMXZ84M	Approved	Malathion decreases the expression of Calcium-activated potassium channel subunit alpha-1 (KCNMA1).	[12]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Calcium-activated potassium channel subunit alpha-1 (KCNMA1).	[13]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Calcium-activated potassium channel subunit alpha-1 (KCNMA1).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Calcium-activated potassium channel subunit alpha-1 (KCNMA1).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Calcium-activated potassium channel subunit alpha-1 (KCNMA1).	[17]
iberiotoxin	DMRIG3O	Investigative	iberiotoxin decreases the activity of Calcium-activated potassium channel subunit alpha-1 (KCNMA1).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Calcium-activated potassium channel subunit alpha-1 (KCNMA1).	[6]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Calcium-activated potassium channel subunit alpha-1 (KCNMA1).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Calcium-activated potassium channel subunit alpha-1 (KCNMA1).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Calcium-activated potassium channel subunit alpha-1 (KCNMA1).	[11]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [3] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [4] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [5] Differential effects of estrogen and progesterone on potassium channels expressed in Xenopus oocytes. Steroids. 2008 Mar;73(3):272-9. doi: 10.1016/j.steroids.2007.10.010. Epub 2007 Nov 4.
• [6] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [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] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [9] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [10] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [11] 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.
• [12] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [13] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [14] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [15] 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.
• [16] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [17] 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.
• [18] The intermediate conductance Ca2+-activated K+ channel inhibitor TRAM-34 stimulates proliferation of breast cancer cells via activation of oestrogen receptors. Br J Pharmacol. 2010 Feb 1;159(3):650-8. doi: 10.1111/j.1476-5381.2009.00557.x. Epub 2009 Dec 24.
• [19] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.
• [20] BK channels in rat and human pulmonary smooth muscle cells are BK-(1) functional complexes lacking the oxygen-sensitive stress axis regulated exon insert. Pulm Circ. 2016 Dec;6(4):563-575. doi: 10.1086/688838.