Target Information

Target General Infomation
Target ID
T24793
Former ID
TTDR00620
Target Name
Voltage-dependent L-type calcium channel alpha-1D subunit
Gene Name
CACNA1D
Synonyms
Calcium channel, L type, alpha-1 polypeptide, isoform 2; Voltage-gated L-type Ca2+ channel alpha1D; Voltage-gated calcium channel alpha subunit Cav1.3; CACNA1D
Target Type
Clinical Trial
Disease Cardiac failure [ICD10: I50]
Heart arrhythmia [ICD10: I47-I49]
Neurological disease [ICD9: 338, 338.2, 410, 782.3,780; ICD10: I21, I22, R52, R52.1-R52.2, R60.9, G89]
Reperfusion injury [ICD10: I00-I99]
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, cell division and cell death. The isoform alpha-1D gives rise to L-type calcium currents. Long-lasting (L-type) calcium channels belong to the 'high-voltage activated' (HVA) group. They are blocked by dihydropyridines (DHP), phenylalkylamines, benzothiazepines, and by omega-agatoxin-IIIA (omega-Aga-IIIA). They are however insensitive to omega-conotoxin- GVIA (omega-CTx-GVIA) and omega-agatoxin-IVA (omega-Aga-IVA).
BioChemical Class
Calcium channel
Target Validation
T24793
UniProt ID
Q01668
Sequence
MMMMMMMKKMQHQRQQQADHANEANYARGTRLPLSGEGPTSQPNSSKQTVLSWQAAIDAA
RQAKAAQTMSTSAPPPVGSLSQRKRQQYAKSKKQGNSSNSRPARALFCLSLNNPIRRACI
SIVEWKPFDIFILLAIFANCVALAIYIPFPEDDSNSTNHNLEKVEYAFLIIFTVETFLKI
IAYGLLLHPNAYVRNGWNLLDFVIVIVGLFSVILEQLTKETEGGNHSSGKSGGFDVKALR
AFRVLRPLRLVSGVPSLQVVLNSIIKAMVPLLHIALLVLFVIIIYAIIGLELFIGKMHKT
CFFADSDIVAEEDPAPCAFSGNGRQCTANGTECRSGWVGPNGGITNFDNFAFAMLTVFQC
ITMEGWTDVLYWMNDAMGFELPWVYFVSLVIFGSFFVLNLVLGVLSGEFSKEREKAKARG
DFQKLREKQQLEEDLKGYLDWITQAEDIDPENEEEGGEEGKRNTSMPTSETESVNTENVS
GEGENRGCCGSLCQAISKSKLSRRWRRWNRFNRRRCRAAVKSVTFYWLVIVLVFLNTLTI
SSEHYNQPDWLTQIQDIANKVLLALFTCEMLVKMYSLGLQAYFVSLFNRFDCFVVCGGIT
ETILVELEIMSPLGISVFRCVRLLRIFKVTRHWTSLSNLVASLLNSMKSIASLLLLLFLF
IIIFSLLGMQLFGGKFNFDETQTKRSTFDNFPQALLTVFQILTGEDWNAVMYDGIMAYGG
PSSSGMIVCIYFIILFICGNYILLNVFLAIAVDNLADAESLNTAQKEEAEEKERKKIARK
ESLENKKNNKPEVNQIANSDNKVTIDDYREEDEDKDPYPPCDVPVGEEEEEEEEDEPEVP
AGPRPRRISELNMKEKIAPIPEGSAFFILSKTNPIRVGCHKLINHHIFTNLILVFIMLSS
AALAAEDPIRSHSFRNTILGYFDYAFTAIFTVEILLKMTTFGAFLHKGAFCRNYFNLLDM
LVVGVSLVSFGIQSSAISVVKILRVLRVLRPLRAINRAKGLKHVVQCVFVAIRTIGNIMI
VTTLLQFMFACIGVQLFKGKFYRCTDEAKSNPEECRGLFILYKDGDVDSPVVRERIWQNS
DFNFDNVLSAMMALFTVSTFEGWPALLYKAIDSNGENIGPIYNHRVEISIFFIIYIIIVA
FFMMNIFVGFVIVTFQEQGEKEYKNCELDKNQRQCVEYALKARPLRRYIPKNPYQYKFWY
VVNSSPFEYMMFVLIMLNTLCLAMQHYEQSKMFNDAMDILNMVFTGVFTVEMVLKVIAFK
PKGYFSDAWNTFDSLIVIGSIIDVALSEADPTESENVPVPTATPGNSEESNRISITFFRL
FRVMRLVKLLSRGEGIRTLLWTFIKSFQALPYVALLIAMLFFIYAVIGMQMFGKVAMRDN
NQINRNNNFQTFPQAVLLLFRCATGEAWQEIMLACLPGKLCDPESDYNPGEEYTCGSNFA
IVYFISFYMLCAFLIINLFVAVIMDNFDYLTRDWSILGPHHLDEFKRIWSEYDPEAKGRI
KHLDVVTLLRRIQPPLGFGKLCPHRVACKRLVAMNMPLNSDGTVMFNATLFALVRTALKI
KTEGNLEQANEELRAVIKKIWKKTSMKLLDQVVPPAGDDEVTVGKFYATFLIQDYFRKFK
KRKEQGLVGKYPAKNTTIALQAGLRTLHDIGPEIRRAISCDLQDDEPEETKREEEDDVFK
RNGALLGNHVNHVNSDRRDSLQQTNTTHRPLHVQRPSIPPASDTEKPLFPPAGNSVCHNH
HNHNSIGKQVPTSTNANLNNANMSKAAHGKRPSIGNLEHVSENGHHSSHKHDREPQRRSS
VKRTRYYETYIRSDSGDEQLPTICREDPEIHGYFRDPHCLGEQEYFSSEECYEDDSSPTW
SRQNYGYYSRYPGRNIDSERPRGYHHPQGFLEDDDSPVCYDSRRSPRRRLLPPTPASHRR
SSFNFECLRRQSSQEEVPSSPIFPHRTALPLHLMQQQIMAVAGLDSSKAQKYSPSHSTRS
WATPPATPPYRDWTPCYTPLIQVEQSEALDQVNGSLPSLHRSSWYTDEPDISYRTFTPAS
LTVPSSFRNKNSDKQRSADSLVEAVLISEGLGRYARDPKFVSATKHEIADACDLTIDEME
SAASTLLNGNVRPRANGDVGPLSHRQDYELQDFGPGYSDEEPDPGRDEEDLADEMICITT
L
Drugs and Mode of Action
Drug(s) NILVADIPINE Drug Info Phase 3 Discovery agent [524577]
SIPATRIGINE Drug Info Discontinued in Phase 2 Neurological disease [545614]
CGS-27830 Drug Info Terminated Discovery agent [545827]
SNAP-5089 Drug Info Terminated Heart arrhythmia [468115], [546179]
TH-9229 Drug Info Terminated Reperfusion injury [546444]
Activator (-)-(S)-BayK8644 Drug Info [543867]
Inhibitor (gating inhibitor) azidopine Drug Info [529818]
[3H](+)-isradipine Drug Info [526019]
Inhibitor CGS-27830 Drug Info [551247]
CV-4093 Drug Info [533081]
MEBUDIPINE Drug Info [530842]
N,N'-Di-acenaphthen-5-yl-guanidine Drug Info [551286]
NILVADIPINE Drug Info [533081]
PD-32577 Drug Info [525576]
SIPATRIGINE Drug Info [551286]
SNAP-5089 Drug Info [533719]
Modulator CPU-228 Drug Info [543867]
TH-9229 Drug Info [546445]
Pathways
KEGG Pathway MAPK signaling pathway
Calcium signaling pathway
cGMP-PKG signaling pathway
cAMP signaling pathway
Cardiac muscle contraction
Adrenergic signaling in cardiomyocytes
Vascular smooth muscle contraction
Circadian entrainment
Retrograde endocannabinoid signaling
Glutamatergic synapse
Cholinergic synapse
Serotonergic synapse
GABAergic synapse
Dopaminergic synapse
Insulin secretion
GnRH signaling pathway
Oxytocin signaling pathway
Type II diabetes mellitus
Carbohydrate digestion and absorption
Alzheimer&#039
s disease
Amphetamine addiction
Hypertrophic cardiomyopathy (HCM)
Arrhythmogenic right ventricular cardiomyopathy (ARVC)
Dilated cardiomyopathy
PANTHER Pathway Alzheimer disease-amyloid secretase pathway
Nicotinic acetylcholine receptor signaling pathway
5HT2 type receptor mediated signaling pathway
Beta1 adrenergic receptor signaling pathway
Beta2 adrenergic receptor signaling pathway
Oxytocin receptor mediated signaling pathway
Reactome Adrenaline,noradrenaline inhibits insulin secretion
NCAM1 interactions
Regulation of insulin secretion
WikiPathways Calcium Regulation in the Cardiac Cell
Arrhythmogenic Right Ventricular Cardiomyopathy
Alzheimers Disease
NCAM signaling for neurite out-growth
Integration of energy metabolism
References
Ref 468115(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: 498).
Ref 524577ClinicalTrials.gov (NCT02017340) A Phase III Trial of Nilvadipine to Treat Alzheimer's Disease. U.S. National Institutes of Health.
Ref 545614Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003904)
Ref 545827Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800004940)
Ref 546179Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800006771)
Ref 546444Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800008159)
Ref 525576Bioorg Med Chem Lett. 1999 Aug 16;9(16):2447-52.Synthesis and biological activity of substituted bis-(4-hydroxyphenyl)methanes as N-type calcium channel blockers.
Ref 526019Alpha 1D (Cav1.3) subunits can form l-type Ca2+ channels activating at negative voltages. J Biol Chem. 2001 Jun 22;276(25):22100-6. Epub 2001 Apr 2.
Ref 529818Expression and 1,4-dihydropyridine-binding properties of brain L-type calcium channel isoforms. Mol Pharmacol. 2009 Feb;75(2):407-14.
Ref 530842Bioorg Med Chem. 2010 May 1;18(9):3147-58. Epub 2010 Mar 19.Antagonism of 4-substituted 1,4-dihydropyridine-3,5-dicarboxylates toward voltage-dependent L-type Ca2+ channels Ca V 1.3 and Ca V 1.2.
Ref 533081J Med Chem. 1989 Oct;32(10):2399-406.Dihydropyrimidines: novel calcium antagonists with potent and long-lasting vasodilative and antihypertensive activity.
Ref 533719J Med Chem. 1995 May 12;38(10):1579-81.Discovery of alpha 1a-adrenergic receptor antagonists based on the L-type Ca2+ channel antagonist niguldipine.
Ref 543867(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: 530).
Ref 546445Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800008159)
Ref 551247CGS 27830, a potent nonpeptide endothelin receptor antagonist, Bioorg. Med. Chem. Lett. 3(10):2099-2104 (1993).
Ref 551286Synthesis and characterization of N-(acenaphth-5-yl)-N'-(4-methoxynaphth-1-yl)guanidine as a glutamate release inhibitor and potential anti-ischemic agent, Bioorg. Med. Chem. Lett. 5(19):2259-2262 (1995).

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