Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY4BLOJ)

• DOT Name: Kv channel-interacting protein 2 (KCNIP2)
• Synonyms: KChIP2; A-type potassium channel modulatory protein 2; Cardiac voltage-gated potassium channel modulatory subunit; Potassium channel-interacting protein 2
• Gene Name: KCNIP2
• Related Disease:
  Atrial fibrillation
  Cardiac disease
  Cardiac failure
  Chronic kidney disease
  Congestive heart failure
  Heart valve disorder
  Myocardial infarction
  Neuralgia
  Arrhythmia
  Ventricular tachycardia
• UniProt ID: KCIP2_HUMAN
• PDB ID: 7UKH; 7W6S
• Pfam ID: PF13499 ; PF13833
• Sequence:
  MRGQGRKESLSDSRDLDGSYDQLTGHPPGPTKKALKQRFLKLLPCCGPQALPSVSETLAA
  PASLRPHRPRLLDPDSVDDEFELSTVCHRPEGLEQLQEQTKFTRKELQVLYRGFKNECPS
  GIVNEENFKQIYSQFFPQGDSSTYATFLFNAFDTNHDGSVSFEDFVAGLSVILRGTVDDR
  LNWAFNLYDLNKDGCITKEEMLDIMKSIYDMMGKYTYPALREEAPREHVESFFQKMDRNK
  DGVVTIEEFIESCQKDENIMRSMQLFDNVI
• Function: Regulatory subunit of Kv4/D (Shal)-type voltage-gated rapidly inactivating A-type potassium channels. Modulates channel density, inactivation kinetics and rate of recovery from inactivation in a calcium-dependent and isoform-specific manner. In vitro, modulates KCND2/Kv4.2 and KCND3/Kv4.3 currents. Involved in KCND2 and KCND3 trafficking to the cell surface. May be required for the expression of I(To) currents in the heart.
• Tissue Specificity: Expressed in brain. Colocalizes with KCND2 in excitatory neurons including cortical and hippocampal CA1 pyramidal cells. Isoform 3 is expressed in heart and in umbilical vein endothelial cells. Not expressed in fetal heart.
• Reactome Pathway: Phase 1 - inactivation of fast Na+ channels (R-HSA-5576894)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Atrial fibrillation	DIS15W6U	Strong	Altered Expression	[1]
Cardiac disease	DISVO1I5	Strong	Biomarker	[2]
Cardiac failure	DISDC067	Strong	Altered Expression	[3]
Chronic kidney disease	DISW82R7	Strong	Altered Expression	[4]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[3]
Heart valve disorder	DIS84O7T	Strong	Altered Expression	[1]
Myocardial infarction	DIS655KI	Strong	Altered Expression	[5]
Neuralgia	DISWO58J	Strong	Biomarker	[6]
Arrhythmia	DISFF2NI	Limited	Biomarker	[7]
Ventricular tachycardia	DISIBXJ3	Limited	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Kv channel-interacting protein 2 (KCNIP2).	[8]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Kv channel-interacting protein 2 (KCNIP2).	[9]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Kv channel-interacting protein 2 (KCNIP2).	[10]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Kv channel-interacting protein 2 (KCNIP2).	[11]

2 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 Kv channel-interacting protein 2 (KCNIP2).	[12]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the methylation of Kv channel-interacting protein 2 (KCNIP2).	[13]

References

• [1] Remodeling of ion channel expression in patients with chronic atrial fibrillation and mitral valvular heart disease.Korean J Intern Med. 2010 Dec;25(4):377-85. doi: 10.3904/kjim.2010.25.4.377. Epub 2010 Nov 27.
• [2] KChIP2 is a core transcriptional regulator of cardiac excitability.Elife. 2017 Mar 6;6:e17304. doi: 10.7554/eLife.17304.
• [3] Loss of H3K4 methylation destabilizes gene expression patterns and physiological functions in adult murine cardiomyocytes.J Clin Invest. 2011 Jul;121(7):2641-50. doi: 10.1172/JCI44641. Epub 2011 Jun 6.
• [4] Electronegative LDL-mediated cardiac electrical remodeling in a rat model of chronic kidney disease.Sci Rep. 2017 Jan 17;7:40676. doi: 10.1038/srep40676.
• [5] Neuropilin 1 ameliorates electrical remodeling at infarct border zones in rats after myocardial infarction.Auton Neurosci. 2018 Nov;214:19-23. doi: 10.1016/j.autneu.2018.08.001. Epub 2018 Aug 9.
• [6] K(+) Channel Modulatory Subunits KChIP and DPP Participate in Kv4-Mediated Mechanical Pain Control.J Neurosci. 2017 Apr 19;37(16):4391-4404. doi: 10.1523/JNEUROSCI.1619-16.2017. Epub 2017 Mar 22.
• [7] A defect in the Kv channel-interacting protein 2 (KChIP2) gene leads to a complete loss of I(to) and confers susceptibility to ventricular tachycardia.Cell. 2001 Dec 14;107(6):801-13. doi: 10.1016/s0092-8674(01)00588-8.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [10] Cardiac toxicity from ethanol exposure in human-induced pluripotent stem cell-derived cardiomyocytes. Toxicol Sci. 2019 May 1;169(1):280-292.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] 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.
• [13] Pregnancy exposure to synthetic phenols and placental DNA methylation - An epigenome-wide association study in male infants from the EDEN cohort. Environ Pollut. 2021 Dec 1;290:118024. doi: 10.1016/j.envpol.2021.118024. Epub 2021 Aug 21.