Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGUNHB3)

• DOT Name: Potassium voltage-gated channel subfamily C member 2 (KCNC2)
• Synonyms: Shaw-like potassium channel; Voltage-gated potassium channel Kv3.2
• Gene Name: KCNC2
• Related Disease:
  Infantile spasm
  Developmental and epileptic encephalopathy 103
• UniProt ID: KCNC2_HUMAN
• Pfam ID: PF02214 ; PF00520
• Sequence:
  MGKIENNERVILNVGGTRHETYRSTLKTLPGTRLALLASSEPPGDCLTTAGDKLQPSPPP
  LSPPPRAPPLSPGPGGCFEGGAGNCSSRGGRASDHPGGGREFFFDRHPGVFAYVLNYYRT
  GKLHCPADVCGPLFEEELAFWGIDETDVEPCCWMTYRQHRDAEEALDIFETPDLIGGDPG
  DDEDLAAKRLGIEDAAGLGGPDGKSGRWRRLQPRMWALFEDPYSSRAARFIAFASLFFIL
  VSITTFCLETHEAFNIVKNKTEPVINGTSVVLQYEIETDPALTYVEGVCVVWFTFEFLVR
  IVFSPNKLEFIKNLLNIIDFVAILPFYLEVGLSGLSSKAAKDVLGFLRVVRFVRILRIFK
  LTRHFVGLRVLGHTLRASTNEFLLLIIFLALGVLIFATMIYYAERVGAQPNDPSASEHTQ
  FKNIPIGFWWAVVTMTTLGYGDMYPQTWSGMLVGALCALAGVLTIAMPVPVIVNNFGMYY
  SLAMAKQKLPRKRKKHIPPAPQASSPTFCKTELNMACNSTQSDTCLGKDNRLLEHNRSVL
  SGDDSTGSEPPLSPPERLPIRRSSTRDKNRRGETCFLLTTGDYTCASDGGIRKGYEKSRS
  LNNIAGLAGNALRLSPVTSPYNSPCPLRRSRSPIPSIL
• Function: Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes, primarily in the brain. Contributes to the regulation of the fast action potential repolarization and in sustained high-frequency firing in neurons of the central nervous system. Homotetramer channels mediate delayed-rectifier voltage-dependent potassium currents that activate rapidly at high-threshold voltages and inactivate slowly. Forms tetrameric 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. Can form functional homotetrameric and heterotetrameric channels that contain variable proportions of KCNC1, and possibly other family members as well; channel properties depend on the type of alpha subunits that are part of the channel. Channel properties may be modulated either by the association with ancillary subunits, such as KCNE1, KCNE2 or KCNE3 or indirectly by nitric oxide (NO) through a cGMP- and PKG-mediated signaling cascade, slowing channel activation and deactivation of delayed rectifier potassium channels. Contributes to fire sustained trains of very brief action potentials at high frequency in retinal ganglion cells, thalamocortical and suprachiasmatic nucleus (SCN) neurons and in hippocampal and neocortical interneurons. Sustained maximal action potential firing frequency in inhibitory hippocampal interneurons is negatively modulated by histamine H2 receptor activation in a cAMP- and protein kinase (PKA) phosphorylation-dependent manner. Plays a role in maintaining the fidelity of synaptic transmission in neocortical GABAergic interneurons by generating action potential (AP) repolarization at nerve terminals, thus reducing spike-evoked calcium influx and GABA neurotransmitter release. Required for long-range synchronization of gamma oscillations over distance in the neocortex. Contributes to the modulation of the circadian rhythm of spontaneous action potential firing in suprachiasmatic nucleus (SCN) neurons in a light-dependent manner.
• 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 DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Infantile spasm	DISZSKDG	Definitive	Autosomal dominant	[1]
Developmental and epileptic encephalopathy 103	DISGD1O5	Strong	Autosomal dominant	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Potassium voltage-gated channel subfamily C member 2 (KCNC2).	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Potassium voltage-gated channel subfamily C member 2 (KCNC2).	[4]

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] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [4] 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.