Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTP3CCEH)

• DOT Name: Potassium voltage-gated channel subfamily A member 1 (KCNA1)
• Synonyms: Voltage-gated K(+) channel HuKI; Voltage-gated potassium channel HBK1; Voltage-gated potassium channel subunit Kv1.1
• Gene Name: KCNA1
• Related Disease:
  Episodic ataxia type 1
  Infantile spasm
  Isolated autosomal dominant hypomagnesemia, Glaudemans type
  Obsolete episodic kinesigenic dyskinesia 1
• UniProt ID: KCNA1_HUMAN
• Pfam ID: PF02214 ; PF00520
• Sequence:
  MTVMSGENVDEASAAPGHPQDGSYPRQADHDDHECCERVVINISGLRFETQLKTLAQFPN
  TLLGNPKKRMRYFDPLRNEYFFDRNRPSFDAILYYYQSGGRLRRPVNVPLDMFSEEIKFY
  ELGEEAMEKFREDEGFIKEEERPLPEKEYQRQVWLLFEYPESSGPARVIAIVSVMVILIS
  IVIFCLETLPELKDDKDFTGTVHRIDNTTVIYNSNIFTDPFFIVETLCIIWFSFELVVRF
  FACPSKTDFFKNIMNFIDIVAIIPYFITLGTEIAEQEGNQKGEQATSLAILRVIRLVRVF
  RIFKLSRHSKGLQILGQTLKASMRELGLLIFFLFIGVILFSSAVYFAEAEEAESHFSSIP
  DAFWWAVVSMTTVGYGDMYPVTIGGKIVGSLCAIAGVLTIALPVPVIVSNFNYFYHRETE
  GEEQAQLLHVSSPNLASDSDLSRRSSSTMSKSEYMEIEEDMNNSIAHYRQVNIRTANCTT
  ANQNCVNKSKLLTDV
• 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 kidney. Contributes to the regulation of the membrane potential and nerve signaling, and prevents neuronal hyperexcitability. 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 KCNA1 forms a delayed-rectifier potassium channel that opens in response to membrane depolarization, followed by slow spontaneous channel closure. In contrast, a heterotetrameric channel formed by KCNA1 and KCNA4 shows rapid inactivation. Regulates neuronal excitability in hippocampus, especially in mossy fibers and medial perforant path axons, preventing neuronal hyperexcitability. Response to toxins that are selective for KCNA1, respectively for KCNA2, suggests that heteromeric potassium channels composed of both KCNA1 and KCNA2 play a role in pacemaking and regulate the output of deep cerebellar nuclear neurons. 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) release. Plays a role in regulating the generation of action potentials and preventing hyperexcitability in myelinated axons of the vagus nerve, and thereby contributes to the regulation of heart contraction. Required for normal neuromuscular responses. Regulates the frequency of neuronal action potential firing in response to mechanical stimuli, and plays a role in the perception of pain caused by mechanical stimuli, but does not play a role in the perception of pain due to heat stimuli. Required for normal responses to auditory stimuli and precise location of sound sources, but not for sound perception. The use of toxins that block specific channels suggest that it contributes to the regulation of the axonal release of the neurotransmitter dopamine. Required for normal postnatal brain development and normal proliferation of neuronal precursor cells in the brain. Plays a role in the reabsorption of Mg(2+) in the distal convoluted tubules in the kidney and in magnesium ion homeostasis, probably via its effect on the membrane potential.
• Tissue Specificity: Detected adjacent to nodes of Ranvier in juxtaparanodal zones in spinal cord nerve fibers, but also in paranodal regions in some myelinated spinal cord axons (at protein level) . Detected in the islet of Langerhans .
• Reactome Pathway: Voltage gated Potassium channels (R-HSA-1296072)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Episodic ataxia type 1	DISB8Z7H	Definitive	Autosomal dominant	[1]
Infantile spasm	DISZSKDG	Supportive	Autosomal dominant	[2]
Isolated autosomal dominant hypomagnesemia, Glaudemans type	DIS97M1E	Supportive	Autosomal dominant	[3]
Obsolete episodic kinesigenic dyskinesia 1	DISRYM2O	Supportive	Autosomal dominant	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Potassium voltage-gated channel subfamily A member 1 (KCNA1).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Potassium voltage-gated channel subfamily A member 1 (KCNA1).	[6]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Potassium voltage-gated channel subfamily A member 1 (KCNA1).	[7]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Potassium voltage-gated channel subfamily A member 1 (KCNA1).	[8]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Potassium voltage-gated channel subfamily A member 1 (KCNA1).	[10]

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 1 (KCNA1).	[9]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
[14C]TEA	DM6SFYH	Investigative	[14C]TEA affects the binding of Potassium voltage-gated channel subfamily A member 1 (KCNA1).	[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] De novo KCNA1 variants in the PVP motif cause infantile epileptic encephalopathy and cognitive impairment similar to recurrent KCNA2 variants. Am J Med Genet A. 2018 Aug;176(8):1748-1752. doi: 10.1002/ajmg.a.38840. Epub 2018 Jul 28.
• [3] A missense mutation in the Kv1.1 voltage-gated potassium channel-encoding gene KCNA1 is linked to human autosomal dominant hypomagnesemia. J Clin Invest. 2009 Apr;119(4):936-42. doi: 10.1172/JCI36948. Epub 2009 Mar 23.
• [4] Familial paroxysmal kinesigenic dyskinesia is associated with mutations in the KCNA1 gene. Hum Mol Genet. 2018 Feb 15;27(4):625-637. doi: 10.1093/hmg/ddx430.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] Evaluation of a human iPSC-derived BBB model for repeated dose toxicity testing with cyclosporine A as model compound. Toxicol In Vitro. 2021 Jun;73:105112. doi: 10.1016/j.tiv.2021.105112. Epub 2021 Feb 22.
• [7] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] Variability of Potassium Channel Blockers in Mesobuthus eupeus Scorpion Venom with Focus on Kv1.1: AN INTEGRATED TRANSCRIPTOMIC AND PROTEOMIC STUDY. J Biol Chem. 2015 May 8;290(19):12195-209. doi: 10.1074/jbc.M115.637611. Epub 2015 Mar 19.