Target Information

Target General Infomation
Target ID
T17569
Former ID
TTDC00303
Target Name
Potassium voltage-gated channel subfamily A member 5
Gene Name
KCNA5
Synonyms
02-Sensitive Potassium Channel Kv1.5; HK2; HPCN1; Potassium channel Kv1.5; Voltage-gatedpotassium channel subunit Kv1.5; KCNA5
Target Type
Successful
Disease Atrial fibrillation [ICD9: 272, 427.31; ICD10: E78, I48]
Angina pectoris [ICD9: 413; ICD10: I20]
Arrhythmia [ICD9: 427; ICD10: I47-I49]
Pain [ICD9: 338, 356.0, 356.8,780; ICD10: G64, G90.0, R52, G89]
Function
Voltage-gatedpotassium channel that mediates transmembrane potassium transport in excitable membranes. 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, and possibly other family members as well; channel properties depend on the type of alpha subunits that are part of the channel (PubMed:12130714). Channel properties are modulated by cytoplasmic beta subunits that regulate the subcellular location of the alpha subunits and promote rapid inactivation (PubMed:12130714). Homotetrameric channels display rapid activation and slow inactivation (PubMed:8505626, PubMed:12130714). May play a role in regulating the secretion of insulin in normal pancreatic islets. Isoform2 exhibits a voltage-dependent recovery from inactivation and an excessive cumulative inactivation (PubMed:11524461).
BioChemical Class
Voltage-gated ion channel
Target Validation
T17569
UniProt ID
P22460
Sequence
MEIALVPLENGGAMTVRGGDEARAGCGQATGGELQCPPTAGLSDGPKEPAPKGRGAQRDA
DSGVRPLPPLPDPGVRPLPPLPEELPRPRRPPPEDEEEEGDPGLGTVEDQALGTASLHHQ
RVHINISGLRFETQLGTLAQFPNTLLGDPAKRLRYFDPLRNEYFFDRNRPSFDGILYYYQ
SGGRLRRPVNVSLDVFADEIRFYQLGDEAMERFREDEGFIKEEEKPLPRNEFQRQVWLIF
EYPESSGSARAIAIVSVLVILISIITFCLETLPEFRDERELLRHPPAPHQPPAPAPGANG
SGVMAPPSGPTVAPLLPRTLADPFFIVETTCVIWFTFELLVRFFACPSKAGFSRNIMNII
DVVAIFPYFITLGTELAEQQPGGGGGGQNGQQAMSLAILRVIRLVRVFRIFKLSRHSKGL
QILGKTLQASMRELGLLIFFLFIGVILFSSAVYFAEADNQGTHFSSIPDAFWWAVVTMTT
VGYGDMRPITVGGKIVGSLCAIAGVLTIALPVPVIVSNFNYFYHRETDHEEPAVLKEEQG
TQSQGPGLDRGVQRKVSGSRGSFCKAGGTLENADSARRGSCPLEKCNVKAKSNVDLRRSL
YALCLDTSRETDL
Drugs and Mode of Action
Drug(s) Dronedarone Drug Info Approved Angina pectoris [1], [2]
BMS-919373 Drug Info Phase 2 Atrial fibrillation [3]
BMS-394136 Drug Info Phase 1 Arrhythmia [4]
IQB-9302 Drug Info Phase 1 Pain [5]
XEN-D0101 Drug Info Phase 1 Atrial fibrillation [6]
XEN-D0103 Drug Info Phase 1 Atrial fibrillation [7]
Dronedarone Drug Info Withdrawn from market Atrial fibrillation [8], [1]
Zatebradine Drug Info Terminated Angina pectoris [9], [10]
Inhibitor 2-amino-2-phenyl-1,1-di(pyridin-3-yl)ethanol Drug Info [11]
2-morpholino-1,1,2-triphenylethanol Drug Info [11]
2-morpholino-1,1-di(pyridin-3-yl)hexan-1-ol Drug Info [11]
2-morpholino-1,1-di(pyridin-3-yl)octan-1-ol Drug Info [11]
2-morpholino-2-phenyl-1,1-di(pyridin-3-yl)ethanol Drug Info [11]
2-phenoxy-1-(2-p-tolylthiazolidin-3-yl)ethanone Drug Info [12]
2-phenyl-1,1-di(pyridin-3-yl)ethanol Drug Info [11]
3-(4-methoxybenzyloxy)-2-phenylthiazolidin-4-one Drug Info [12]
3-(benzyloxy)-2-(4-chlorophenyl)thiazolidin-4-one Drug Info [12]
3-methyl-2-morpholino-1,1-diphenylbutan-1-ol Drug Info [11]
4-(4-phenoxybutoxy)-7H-furo[3,2-g]chromen-7-one Drug Info [13]
BMS-919373 Drug Info [14]
N-Benzyl-2-(toluene-4-sulfonylamino)-benzamide Drug Info [15]
N-Phenethyl-2-(toluene-4-sulfonylamino)-benzamide Drug Info [15]
XEN-D0103 Drug Info [16]
Modulator BMS-394136 Drug Info [17]
XEN-D0101 Drug Info [18]
Zatebradine Drug Info
Blocker (channel blocker) clofilium Drug Info [19]
tetraethylammonium Drug Info [20]
Antagonist DPO-1 Drug Info [16]
Blocker Dronedarone Drug Info [8]
NIP-142 Drug Info [8]
RS-100302 Drug Info [8]
S-20951 Drug Info [8]
S-9947 Drug Info [8]
Opener IQB-9302 Drug Info [5]
XEN-D0104 Drug Info [16]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
PathWhiz Pathway Muscle/Heart Contraction
Reactome Voltage gated Potassium channels
WikiPathways Potassium Channels
References
REF 1(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7465).
REF 2Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
REF 3ClinicalTrials.gov (NCT02156076) A Blinded Study to Evaluate Effect on Atrial Fibrillation Burden in Patients With Paroxysmal Atrial Fibrillation. U.S. National Institutes of Health.
REF 4ClinicalTrials.gov (NCT00162448) A Phase I Study to Assess the Electrophysiologic Effects of BMS-394136 on the Atrium and Ventricle in Patients With Dual-Chamber Pacemakers or Defibrillators. U.S. National Institutes of Health.
REF 5Stereoselective effects of the enantiomers of a new local anaesthetic, IQB-9302, on a human cardiac potassium channel (Kv1.5). Br J Pharmacol. 2001 Jan;132(2):385-92.
REF 6Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800018084)
REF 7ClinicalTrials.gov (NCT02390258) Fed-Fasted, Single and Multiple Ascending Dose Trial of XEN-D0103. U.S. National Institutes of Health.
REF 8New antiarrhythmic agents for atrial fibrillation and atrial flutter. Expert Opin Emerg Drugs. 2005 May;10(2):311-22.
REF 9(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 2358).
REF 10Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000429)
REF 11Bioorg Med Chem Lett. 2010 Apr 15;20(8):2493-6. Epub 2010 Mar 4.Discovery of triarylethanolamine inhibitors of the Kv1.5 potassium channel.
REF 12Bioorg Med Chem Lett. 2007 Jan 1;17(1):282-4. Epub 2006 Nov 13.Evolution of thiazolidine-based blockers of human Kv1.5 for the treatment of atrial arrhythmias.
REF 13Bioorg Med Chem Lett. 2010 Dec 1;20(23):6989-92. Epub 2010 Oct 23.Substituted N-{3-[(1,1-dioxido-1,2-benzothiazol-3-yl)(phenyl)amino]propyl}benzamide analogs as potent Kv1.3 ion channel blockers. Part 2.
REF 14Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800035504)
REF 15Bioorg Med Chem Lett. 2004 Jun 7;14(11):2823-7.Pharmacophore-based search, synthesis, and biological evaluation of anthranilic amides as novel blockers of the Kv1.5 channel.
REF 16(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 542).
REF 17Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
REF 18Human electrophysiological and pharmacological properties of XEN-D0101: a novel atrial-selective Kv1.5/IKur inhibitor. J Cardiovasc Pharmacol. 2013 May;61(5):408-15.
REF 19Mechanism of clofilium block of the human Kv1.5 delayed rectifier potassium channel. Mol Pharmacol. 1995 Jan;47(1):198-205.
REF 20Pharmacological characterization of five cloned voltage-gated K+ channels, types Kv1.1, 1.2, 1.3, 1.5, and 3.1, stably expressed in mammalian cell lines. Mol Pharmacol. 1994 Jun;45(6):1227-34.

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