Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT5OEKU)

• DTT Name: Voltage-gated potassium channel Kv2.1 (KCNB1)
• Synonyms: Voltage-gated potassium channel subunit Kv2.1; Rectifier potassium channel Kv2.1; Potassium voltage-gated channel subfamily B member 1; Potassium channel Kv2.1; H-DRK1; DRK1
• Gene Name: KCNB1
• DTT Type: Literature-reported target; [1]
• BioChemical Class: Voltage-gated ion channel
• UniProt ID: KCNB1_HUMAN
• TTD ID: T44516
• Sequence:
  MPAGMTKHGSRSTSSLPPEPMEIVRSKACSRRVRLNVGGLAHEVLWRTLDRLPRTRLGKL
  RDCNTHDSLLEVCDDYSLDDNEYFFDRHPGAFTSILNFYRTGRLHMMEEMCALSFSQELD
  YWGIDEIYLESCCQARYHQKKEQMNEELKREAETLREREGEEFDNTCCAEKRKKLWDLLE
  KPNSSVAAKILAIISIMFIVLSTIALSLNTLPELQSLDEFGQSTDNPQLAHVEAVCIAWF
  TMEYLLRFLSSPKKWKFFKGPLNAIDLLAILPYYVTIFLTESNKSVLQFQNVRRVVQIFR
  IMRILRILKLARHSTGLQSLGFTLRRSYNELGLLILFLAMGIMIFSSLVFFAEKDEDDTK
  FKSIPASFWWATITMTTVGYGDIYPKTLLGKIVGGLCCIAGVLVIALPIPIIVNNFSEFY
  KEQKRQEKAIKRREALERAKRNGSIVSMNMKDAFARSIEMMDIVVEKNGENMGKKDKVQD
  NHLSPNKWKWTKRTLSETSSSKSFETKEQGSPEKARSSSSPQHLNVQQLEDMYNKMAKTQ
  SQPILNTKESAAQSKPKEELEMESIPSPVAPLPTRTEGVIDMRSMSSIDSFISCATDFPE
  ATRFSHSPLTSLPSKTGGSTAPEVGWRGALGASGGRFVEANPSPDASQHSSFFIESPKSS
  MKTNNPLKLRALKVNFMEGDPSPLLPVLGMYHDPLRNRGSAAAAVAGLECATLLDKAVLS
  PESSIYTTASAKTPPRSPEKHTAIAFNFEAGVHQYIDADTDDEGQLLYSVDSSPPKSLPG
  STSPKFSTGTRSEKNHFESSPLPTSPKFLRQNCIYSTEALTGKGPSGQEKCKLENHISPD
  VRVLPGGGAHGSTRDQSI
• Function: Contributes to the regulation of the action potential (AP) repolarization, duration and frequency of repetitive AP firing in neurons, muscle cells and endocrine cells and plays a role in homeostatic attenuation of electrical excitability throughout the brain. Plays also a role in the regulation of exocytosis independently of its electrical function. Forms tetrameric potassium-selective channels through which potassium ions pass in accordance with their electrochemical gradient. The channel alternates between opened and closed conformations in response to the voltage difference across the membrane. Homotetrameric channels mediate a delayed-rectifier voltage-dependent outward potassium current that display rapid activation and slow inactivation in response to membrane depolarization. Can form functional homotetrameric and heterotetrameric channels that contain variable proportions of KCNB2; channel properties depend on the type of alpha subunits that are part of the channel. Can also form functional heterotetrameric channels with other alpha subunits that are non-conducting when expressed alone, such as KCNF1, KCNG1, KCNG3, KCNG4, KCNH1, KCNH2, KCNS1, KCNS2, KCNS3 and KCNV1, creating a functionally diverse range of channel complexes. Heterotetrameric channel activity formed with KCNS3 show increased current amplitude with the threshold for action potential activation shifted towards more negative values in hypoxic-treated pulmonary artery smooth muscle cells. Channel properties are also modulated by cytoplasmic ancillary beta subunits such as AMIGO1, KCNE1, KCNE2 and KCNE3, slowing activation and inactivation rate of the delayed rectifier potassium channels. In vivo, membranes probably contain a mixture of heteromeric potassium channel complexes, making it difficult to assign currents observed in intact tissues to any particular potassium channel family member. Major contributor to the slowly inactivating delayed-rectifier voltage-gated potassium current in neurons of the central nervous system, sympathetic ganglion neurons, neuroendocrine cells, pancreatic beta cells, cardiomyocytes and smooth muscle cells. Mediates the major part of the somatodendritic delayed-rectifier potassium current in hippocampal and cortical pyramidal neurons and sympathetic superior cervical ganglion (CGC) neurons that acts to slow down periods of firing, especially during high frequency stimulation. Plays a role in the induction of long-term potentiation (LTP) of neuron excitability in the CA3 layer of the hippocampus. Contributes to the regulation of glucose-induced action potential amplitude and duration in pancreatic beta cells, hence limiting calcium influx and insulin secretion. Plays a role in the regulation of resting membrane potential and contraction in hypoxia-treated pulmonary artery smooth muscle cells. May contribute to the regulation of the duration of both the action potential of cardiomyocytes and the heart ventricular repolarization QT interval. Contributes to the pronounced pro-apoptotic potassium current surge during neuronal apoptotic cell death in response to oxidative injury. May confer neuroprotection in response to hypoxia/ischemic insults by suppressing pyramidal neurons hyperexcitability in hippocampal and cortical regions. Promotes trafficking of KCNG3, KCNH1 and KCNH2 to the cell surface membrane, presumably by forming heterotetrameric channels with these subunits. Plays a role in the calcium-dependent recruitment and release of fusion-competent vesicles from the soma of neurons, neuroendocrine and glucose-induced pancreatic beta cells by binding key components of the fusion machinery in a pore-independent manner. Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes, primarily in the brain, but also in the pancreas and cardiovascular system.
• Reactome Pathway:
  Glucagon-like Peptide-1 (GLP1) regulates insulin secretion (R-HSA-381676)
  Voltage gated Potassium channels (R-HSA-1296072)

Molecular Interaction Atlas (MIA) of This DTT

4 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
3-bicyclo[2.2.1]hept-2-yl-benzene-1,2-diol	DMZ8WMA	Discovery agent	N.A.	Investigative	[2]
DABCO-C16	DMN3GTF	Discovery agent	N.A.	Investigative	[3]
RY796	DMW4850	Discovery agent	N.A.	Investigative	[1]
[14C]TEA	DM6SFYH	Discovery agent	N.A.	Investigative	[4]

References

• [1] Identification of novel and selective Kv2 channel inhibitors. Mol Pharmacol. 2011 Dec;80(6):959-64.
• [2] Novel neuroprotective K+ channel inhibitor identified by high-throughput screening in yeast. Mol Pharmacol. 2004 Jan;65(1):214-9.
• [3] 1,4-Diazabicyclo[2.2.2]octane derivatives: a novel class of voltage-gated potassium channel blockers. Mol Pharmacol. 2006 Mar;69(3):718-26.
• [4] Modulation of Kv2.1 channel gating and TEA sensitivity by distinct domains of SNAP-25. Biochem J. 2006 Jun 1;396(2):363-9.