Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT1AQ50)

• DTT Name: Charybdotoxin receptor beta-4 (BKbeta4)
• Synonyms: KCNMB4; Calcium activated potassium KCNMA1 (maxiK) channel
• Gene Name: KCNMB4
• DTT Type: Clinical trial target; [1]
• UniProt ID: KCMB4_HUMAN
• TTD ID: T67063
• 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. 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.
• KEGG Pathway:
  cGMP-PKG signaling pathway (hsa04022)
  Vascular smooth muscle contraction (hsa04270)
  Insulin secretion (hsa04911)
  Salivary secretion (hsa04970)
  Pancreatic secretion (hsa04972)
• Reactome Pathway: cGMP effects (R-HSA-418457)

Molecular Interaction Atlas (MIA) of This DTT

1 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BMS-223131	DMJUV6C	Erectile dysfunction	HA01.1	Phase 2	[1]

2 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CNS-1237	DMP3QAZ	Cerebrovascular ischaemia	8B1Z	Terminated	[2]
NS-1619	DMES0OT	Asthma	CA23	Terminated	[3]

4 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
iberiotoxin	DMRIG3O	Discovery agent	N.A.	Investigative	[4]
paxilline	DMPF2N1	Discovery agent	N.A.	Investigative	[5]
slotoxin	DMBD6TC	Discovery agent	N.A.	Investigative	[6]
[14C]TEA	DM6SFYH	Discovery agent	N.A.	Investigative	[4]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Asthma	CA23	Nasal and bronchial airway	5.61E-07	0.26	0.41

References

• [1] Effect of 4-(5-chloro-2-hydroxyphenyl)-3-(2-hydroxyethyl)-6-(trifluoromethyl)-quinolin-2(1H)-one (BMS-223131), a novel opener of large conductance ... J Pharmacol Exp Ther. 2005 May;313(2):840-7.
• [2] Effects of Ca2+ and Na+ channel inhibitors in vitro and in global cerebral ischaemia in vivo. Eur J Pharmacol. 1997 Aug 6;332(2):121-31.
• [3] BK channel activation by NS-1619 is partially mediated by intracellular Ca2+ release in smooth muscle cells of porcine coronary artery
• [4] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 380).
• [5] Paxilline inhibition of the alpha-subunit of the high-conductance calcium-activated potassium channel. Neuropharmacology. 1996;35(7):963-8.
• [6] Slotoxin, alphaKTx1.11, a new scorpion peptide blocker of MaxiK channels that differentiates between alpha and alpha+beta (beta1 or beta4) complexes. FEBS Lett. 2001 Sep 21;505(3):369-73.