Target Information

Target General Infomation
Target ID
T54644
Former ID
TTDS00413
Target Name
Voltage-dependent T-type calcium channel subunit alpha-1H
Gene Name
CACNA1H
Synonyms
KCND3; Voltage-gated potassium channel subunit Kv4.3; CACNA1H
Target Type
Successful
Disease Angina pectoris [ICD9: 413; ICD10: I20]
Cancer [ICD9: 140-229; ICD10: C00-C96]
Insomnia [ICD9: 307.41, 307.42, 327.0, 780.51, 780.52; ICD10: F51.0, G47.0]
Metabolic acidosis [ICD9: 276.2; ICD10: E87.2]
Migraine [ICD9: 346; ICD10: G43]
Ovarian cancer [ICD9: 183; ICD10: C56]
Pain [ICD9: 338, 356.0, 356.8,780; ICD10: G64, G90.0, R52, G89]
Unspecified [ICD code not available]
Function
Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, celldivision and cell death. The isoform alpha-1H gives rise to T-type calcium currents. T-type calcium channels belong to the "low-voltage activated (LVA)" group and are strongly blocked by nickel and mibefradil. A particularity of this type of channels is an opening at quite negative potentials, and a voltage-dependent inactivation. T-type channels serve pacemaking functions in both central neuronsand cardiac nodal cells and support calcium signaling in secretory cells and vascular smooth muscle. They may also be involved in the modulation of firing patterns of neurons which is important for information processing as well as in cell growth processes. .
BioChemical Class
Voltage-gated ion channel
Target Validation
T54644
UniProt ID
O95180
Sequence
MTEGARAADEVRVPLGAPPPGPAALVGASPESPGAPGREAERGSELGVSPSESPAAERGA
ELGADEEQRVPYPALAATVFFCLGQTTRPRSWCLRLVCNPWFEHVSMLVIMLNCVTLGMF
RPCEDVECGSERCNILEAFDAFIFAFFAVEMVIKMVALGLFGQKCYLGDTWNRLDFFIVV
AGMMEYSLDGHNVSLSAIRTVRVLRPLRAINRVPSMRILVTLLLDTLPMLGNVLLLCFFV
FFIFGIVGVQLWAGLLRNRCFLDSAFVRNNNLTFLRPYYQTEEGEENPFICSSRRDNGMQ
KCSHIPGRRELRMPCTLGWEAYTQPQAEGVGAARNACINWNQYYNVCRSGDSNPHNGAIN
FDNIGYAWIAIFQVITLEGWVDIMYYVMDAHSFYNFIYFILLIIVGSFFMINLCLVVIAT
QFSETKQRESQLMREQRARHLSNDSTLASFSEPGSCYEELLKYVGHIFRKVKRRSLRLYA
RWQSRWRKKVDPSAVQGQGPGHRQRRAGRHTASVHHLVYHHHHHHHHHYHFSHGSPRRPG
PEPGACDTRLVRAGAPPSPPSPGRGPPDAESVHSIYHADCHIEGPQERARVAHAAATAAA
SLRLATGLGTMNYPTILPSGVGSGKGSTSPGPKGKWAGGPPGTGGHGPLSLNSPDPYEKI
PHVVGEHGLGQAPGHLSGLSVPCPLPSPPAGTLTCELKSCPYCTRALEDPEGELSGSESG
DSDGRGVYEFTQDVRHGDRWDPTRPPRATDTPGPGPGSPQRRAQQRAAPGEPGWMGRLWV
TFSGKLRRIVDSKYFSRGIMMAILVNTLSMGVEYHEQPEELTNALEISNIVFTSMFALEM
LLKLLACGPLGYIRNPYNIFDGIIVVISVWEIVGQADGGLSVLRTFRLLRVLKLVRFLPA
LRRQLVVLVKTMDNVATFCTLLMLFIFIFSILGMHLFGCKFSLKTDTGDTVPDRKNFDSL
LWAIVTVFQILTQEDWNVVLYNGMASTSSWAALYFVALMTFGNYVLFNLLVAILVEGFQA
EGDANRSDTDEDKTSVHFEEDFHKLRELQTTELKMCSLAVTPNGHLEGRGSLSPPLIMCT
AATPMPTPKSSPFLDAAPSLPDSRRGSSSSGDPPLGDQKPPASLRSSPCAPWGPSGAWSS
RRSSWSSLGRAPSLKRRGQCGERESLLSGEGKGSTDDEAEDGRAAPGPRATPLRRAESLD
PRPLRPAALPPTKCRDRDGQVVALPSDFFLRIDSHREDAAELDDDSEDSCCLRLHKVLEP
YKPQWCRSREAWALYLFSPQNRFRVSCQKVITHKMFDHVVLVFIFLNCVTIALERPDIDP
GSTERVFLSVSNYIFTAIFVAEMMVKVVALGLLSGEHAYLQSSWNLLDGLLVLVSLVDIV
VAMASAGGAKILGVLRVLRLLRTLRPLRVISRAPGLKLVVETLISSLRPIGNIVLICCAF
FIIFGILGVQLFKGKFYYCEGPDTRNISTKAQCRAAHYRWVRRKYNFDNLGQALMSLFVL
SSKDGWVNIMYDGLDAVGVDQQPVQNHNPWMLLYFISFLLIVSFFVLNMFVGVVVENFHK
CRQHQEAEEARRREEKRLRRLERRRRSTFPSPEAQRRPYYADYSPTRRSIHSLCTSHYLD
LFITFIICVNVITMSMEHYNQPKSLDEALKYCNYVFTIVFVFEAALKLVAFGFRRFFKDR
WNQLDLAIVLLSLMGITLEEIEMSAALPINPTIIRIMRVLRIARVLKLLKMATGMRALLD
TVVQALPQVGNLGLLFMLLFFIYAALGVELFGRLECSEDNPCEGLSRHATFSNFGMAFLT
LFRVSTGDNWNGIMKDTLRECSREDKHCLSYLPALSPVYFVTFVLVAQFVLVNVVVAVLM
KHLEESNKEAREDAELDAEIELEMAQGPGSARRVDADRPPLPQESPGARDAPNLVARKVS
VSRMLSLPNDSYMFRPVVPASAPHPRPLQEVEMETYGAGTPLGSVASVHSPPAESCASLQ
IPLAVSSPARSGEPLHALSPRGTARSPSLSRLLCRQEAVHTDSLEGKIDSPRDTLDPAEP
GEKTPVRPVTQGGSLQSPPRSPRPASVRTRKHTFGQRCVSSRPAAPGGEEAEASDPADEE
VSHITSSACPWQPTAEPHGPEASPVAGGERDLRRLYSVDAQGFLDKPGRADEQWRPSAEL
GSGEPGEAKAWGPEAEPALGARRKKKMSPPCISVEPPAEDEGSARPSAAEGGSTTLRRRT
PSCEATPHRDSLEPTEGSGAGGDPAAKGERWGQASCRAEHLTVPSFAFEPLDLGVPSGDP
FLDGSHSVTPESRASSSGAIVPLEPPESEPPMPVGDPPEKRRGLYLTVPQCPLEKPGSPS
ATPAPGGGADDPV
Drugs and Mode of Action
Drug(s) Flunarizine Drug Info Approved Migraine [1]
Sodium bicarbonate Drug Info Approved Metabolic acidosis [2], [3], [4]
ABT-639 Drug Info Phase 2 Pain [5], [6]
TTA-A8 Drug Info Preclinical Insomnia [7], [8]
Mibefradil Drug Info Withdrawn from market Ovarian cancer [9], [10]
U-92032 Drug Info Terminated Discovery agent [11]
Modulator ABT-639 Drug Info [5]
Z 944 Drug Info
Inhibitor Cis-N,5-dibenzyl-6-oxomorpholine-3-carboxamide Drug Info [12]
GNF-PF-1967 Drug Info [13]
GNF-PF-4599 Drug Info [13]
KYS-05001 Drug Info [14]
KYS-05040 Drug Info [14]
KYS-05041 Drug Info [14]
KYS-05042 Drug Info [14]
KYS-05050 Drug Info [15]
KYS-05077 Drug Info [15]
KYS-05080 Drug Info [15]
Mibefradil Drug Info [16]
TTL-1177 Drug Info [17]
U-92032 Drug Info [18]
Blocker DP-3005 Drug Info [17]
Flunarizine Drug Info [19], [20]
HYP-10 Drug Info [17]
Sodium bicarbonate Drug Info [21]
Antagonist KST-5468 Drug Info [17]
TTA-A8 Drug Info [22]
Blocker (channel blocker) ML218 Drug Info [23]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway MAPK signaling pathway
Calcium signaling pathway
Circadian entrainment
PathWhiz Pathway Muscle/Heart Contraction
Reactome NCAM1 interactions
WikiPathways Corticotropin-releasing hormone
NCAM signaling for neurite out-growth
References
REF 1FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 012102.
REF 2(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: 4507).
REF 3FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 018509.
REF 4Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
REF 5Effects of a T-type calcium channel blocker, ABT-639, on spontaneous activity in C-nociceptors in patients with painful diabetic neuropathy: a randomized controlled trial. Pain. 2015 Nov;156(11):2175-83.
REF 6(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: 7721).
REF 7(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: 7724).
REF 8Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800010094)
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: 2522).
REF 10Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000236)
REF 11Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800004258)
REF 12Bioorg Med Chem Lett. 2006 Oct 1;16(19):5244-8. Epub 2006 Jul 28.Morpholin-2-one derivatives as novel selective T-type Ca2+ channel blockers.
REF 13Bioorg Med Chem. 2007 Jan 15;15(2):1091-105. Epub 2006 Oct 30.3D pharmacophore based virtual screening of T-type calcium channel blockers.
REF 14Bioorg Med Chem Lett. 2004 Jul 5;14(13):3379-84.3,4-Dihydroquinazoline derivatives as novel selective T-type Ca2+ channel blockers.
REF 15Bioorg Med Chem Lett. 2007 Jan 15;17(2):471-5. Epub 2006 Oct 12.Synthesis and biological evaluation of novel T-type calcium channel blockers.
REF 16Mibefradil block of cloned T-type calcium channels. J Pharmacol Exp Ther. 2000 Oct;295(1):302-8.
REF 17(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: 536).
REF 18J Med Chem. 2000 Sep 7;43(18):3372-6.Discovery of (2S)-1-(4-amino-2,3,5- trimethylphenoxy)-3-[4-[4-(4- fluorobenzyl)phenyl]-1-piperazinyl]-2-propanol dimethanesulfonate (SUN N8075): a dual Na(+) and Ca(2+) channel blocker with antioxidant activity.
REF 19Migraine prophylaxis with calcium antagonists: a haemodynamic study using transcranial Doppler ultrasound. Rev Neurol. 2004 Feb 16-29;38(4):316-9.
REF 20Positive Allosteric Interaction of Structurally Diverse T-Type Calcium Channel Antagonists. Cell Biochem Biophys. 2009 Jul 7.
REF 21Acute renal failure. Clin Evid (Online). 2008 Sep 3;2008. pii: 2001.
REF 22Short-acting T-type calcium channel antagonists significantly modify sleep architecture in rodents. ACS Med Chem Lett. 2010 Aug 24;1(9):504-9.
REF 23The Discovery and Characterization of ML218: A Novel, Centrally Active T-Type Calcium Channel Inhibitor with Robust Effects in STN Neurons and in a Rodent Model of Parkinson's Disease. ACS Chem Neurosci. 2011 Dec 21;2(12):730-742.

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