Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT18SUP8)

• DOT Name: Potassium voltage-gated channel subfamily A member 2 (KCNA2)
• Synonyms: NGK1; Voltage-gated K(+) channel HuKIV; Voltage-gated potassium channel HBK5; Voltage-gated potassium channel subunit Kv1.2
• Gene Name: KCNA2
• Related Disease:
  Infantile spasm
  Developmental and epileptic encephalopathy, 32
  Undetermined early-onset epileptic encephalopathy
• UniProt ID: KCNA2_HUMAN
• Pfam ID: PF02214 ; PF00520
• Sequence:
  MTVATGDPADEAAALPGHPQDTYDPEADHECCERVVINISGLRFETQLKTLAQFPETLLG
  DPKKRMRYFDPLRNEYFFDRNRPSFDAILYYYQSGGRLRRPVNVPLDIFSEEIRFYELGE
  EAMEMFREDEGYIKEEERPLPENEFQRQVWLLFEYPESSGPARIIAIVSVMVILISIVSF
  CLETLPIFRDENEDMHGSGVTFHTYSNSTIGYQQSTSFTDPFFIVETLCIIWFSFEFLVR
  FFACPSKAGFFTNIMNIIDIVAIIPYFITLGTELAEKPEDAQQGQQAMSLAILRVIRLVR
  VFRIFKLSRHSKGLQILGQTLKASMRELGLLIFFLFIGVILFSSAVYFAEADERESQFPS
  IPDAFWWAVVSMTTVGYGDMVPTTIGGKIVGSLCAIAGVLTIALPVPVIVSNFNYFYHRE
  TEGEEQAQYLQVTSCPKIPSSPDLKKSRSASTISKSDYMEIQEGVNNSNEDFREENLKTA
  NCTLANTNYVNITKMLTDV
• Function: Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes, primarily in the brain and the central nervous system, but also in the cardiovascular system. Prevents aberrant action potential firing and regulates neuronal output. 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. Can form functional homotetrameric channels and heterotetrameric channels that contain variable proportions of KCNA1, KCNA2, KCNA4, KCNA5, KCNA6, KCNA7, and possibly other family members as well; channel properties depend on the type of alpha subunits that are part of the channel. Channel properties are modulated by cytoplasmic beta subunits that regulate the subcellular location of the alpha subunits and promote rapid inactivation of 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. Homotetrameric KCNA2 forms a delayed-rectifier potassium channel that opens in response to membrane depolarization, followed by slow spontaneous channel closure. In contrast, a heteromultimer formed by KCNA2 and KCNA4 shows rapid inactivation. Regulates neuronal excitability and plays a role as pacemaker in the regulation of neuronal action potentials. KCNA2-containing channels play a presynaptic role and prevent hyperexcitability and aberrant action potential firing. Response to toxins that are selective for KCNA2-containing potassium channels suggests that in Purkinje cells, dendritic subthreshold KCNA2-containing potassium channels prevent random spontaneous calcium spikes, suppressing dendritic hyperexcitability without hindering the generation of somatic action potentials, and thereby play an important role in motor coordination. Plays a role in the induction of long-term potentiation of neuron excitability in the CA3 layer of the hippocampus. May function as down-stream effector for G protein-coupled receptors and inhibit GABAergic inputs to basolateral amygdala neurons. May contribute to the regulation of neurotransmitter release, such as gamma-aminobutyric acid (GABA). Contributes to the regulation of the axonal release of the neurotransmitter dopamine. Reduced KCNA2 expression plays a role in the perception of neuropathic pain after peripheral nerve injury, but not acute pain. Plays a role in the regulation of the time spent in non-rapid eye movement (NREM) sleep.
• Tissue Specificity: Detected in brain cortex . Detected in peroneal nerve in the juxtaparanodal regions of the node of Ranvier; expression is decreased in patients with diabetes mellitus that suffer from axonal neuropathy . Detected in paranodal and juxtanodal zones in myelinated spinal cord (at protein level) .
• Reactome Pathway: Voltage gated Potassium channels (R-HSA-1296072)

Molecular Interaction Atlas (MIA) of This DOT

3 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, 32	DISIV4IG	Strong	Autosomal dominant	[2]
Undetermined early-onset epileptic encephalopathy	DISISEI2	Strong	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Potassium voltage-gated channel subfamily A member 2 (KCNA2).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Potassium voltage-gated channel subfamily A member 2 (KCNA2).	[4]
Marinol	DM70IK5	Approved	Marinol increases the expression of Potassium voltage-gated channel subfamily A member 2 (KCNA2).	[5]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Potassium voltage-gated channel subfamily A member 2 (KCNA2).	[7]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Potassium voltage-gated channel subfamily A member 2 (KCNA2).	[8]

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 A member 2 (KCNA2).	[6]

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] Seizures and reduced life span in mice lacking the potassium channel subunit Kv1.2, but hypoexcitability and enlarged Kv1 currents in auditory neurons. J Neurophysiol. 2007 Sep;98(3):1501-25. doi: 10.1152/jn.00640.2006. Epub 2007 Jul 18.
• [3] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [4] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [5] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [6] 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.
• [7] Transcriptomic?pathway?and?benchmark dose analysis of Bisphenol A, Bisphenol S, Bisphenol F, and 3,3',5,5'-Tetrabromobisphenol A in H9 human embryonic stem cells. Toxicol In Vitro. 2021 Apr;72:105097. doi: 10.1016/j.tiv.2021.105097. Epub 2021 Jan 18.
• [8] 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.