Target Information

Target General Information

Target ID

T51115 (Former ID: TTDS00414)

Target Name

Voltage-gated calcium channel alpha Cav1.2 (CACNA1C)

Synonyms

Voltage-gated calcium channel subunit alpha Cav1.2; Voltage-dependent L-type calcium channel subunit alpha-1C; Calcium channel, L type, alpha-1 polypeptide, isoform 1, cardiac muscle; CCHL1A1; CACNL1A1; CACN2; CACH2

Gene Name

CACNA1C

Target Type

Successful target

[1]

Disease

[+] 1 Target-related Diseases

Alzheimer disease [ICD-11: 8A20]

Function

Mediates influx of calcium ions into the cytoplasm, and thereby triggers calcium release from the sarcoplasm. Plays an important role in excitation-contraction coupling in the heart. Required for normal heart development and normal regulation of heart rhythm. Required for normal contraction of smooth muscle cells in blood vessels and in the intestine. Essential for normal blood pressure regulation via its role in the contraction of arterial smooth muscle cells. Long-lasting (L-type) calcium channels belong to the 'high-voltage activated' (HVA) group. Pore-forming, alpha-1C subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents.

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BioChemical Class

Voltage-gated ion channel

UniProt ID

CAC1C_HUMAN

Sequence

MVNENTRMYIPEENHQGSNYGSPRPAHANMNANAAAGLAPEHIPTPGAALSWQAAIDAAR
QAKLMGSAGNATISTVSSTQRKRQQYGKPKKQGSTTATRPPRALLCLTLKNPIRRACISI
VEWKPFEIIILLTIFANCVALAIYIPFPEDDSNATNSNLERVEYLFLIIFTVEAFLKVIA
YGLLFHPNAYLRNGWNLLDFIIVVVGLFSAILEQATKADGANALGGKGAGFDVKALRAFR
VLRPLRLVSGVPSLQVVLNSIIKAMVPLLHIALLVLFVIIIYAIIGLELFMGKMHKTCYN
QEGIADVPAEDDPSPCALETGHGRQCQNGTVCKPGWDGPKHGITNFDNFAFAMLTVFQCI
TMEGWTDVLYWVNDAVGRDWPWIYFVTLIIIGSFFVLNLVLGVLSGEFSKEREKAKARGD
FQKLREKQQLEEDLKGYLDWITQAEDIDPENEDEGMDEEKPRNMSMPTSETESVNTENVA
GGDIEGENCGARLAHRISKSKFSRYWRRWNRFCRRKCRAAVKSNVFYWLVIFLVFLNTLT
IASEHYNQPNWLTEVQDTANKALLALFTAEMLLKMYSLGLQAYFVSLFNRFDCFVVCGGI
LETILVETKIMSPLGISVLRCVRLLRIFKITRYWNSLSNLVASLLNSVRSIASLLLLLFL
FIIIFSLLGMQLFGGKFNFDEMQTRRSTFDNFPQSLLTVFQILTGEDWNSVMYDGIMAYG
GPSFPGMLVCIYFIILFICGNYILLNVFLAIAVDNLADAESLTSAQKEEEEEKERKKLAR
TASPEKKQELVEKPAVGESKEEKIELKSITADGESPPATKINMDDLQPNENEDKSPYPNP
ETTGEEDEEEPEMPVGPRPRPLSELHLKEKAVPMPEASAFFIFSSNNRFRLQCHRIVNDT
IFTNLILFFILLSSISLAAEDPVQHTSFRNHILFYFDIVFTTIFTIEIALKILGNADYVF
TSIFTLEIILKMTAYGAFLHKGSFCRNYFNILDLLVVSVSLISFGIQSSAINVVKILRVL
RVLRPLRAINRAKGLKHVVQCVFVAIRTIGNIVIVTTLLQFMFACIGVQLFKGKLYTCSD
SSKQTEAECKGNYITYKDGEVDHPIIQPRSWENSKFDFDNVLAAMMALFTVSTFEGWPEL
LYRSIDSHTEDKGPIYNYRVEISIFFIIYIIIIAFFMMNIFVGFVIVTFQEQGEQEYKNC
ELDKNQRQCVEYALKARPLRRYIPKNQHQYKVWYVVNSTYFEYLMFVLILLNTICLAMQH
YGQSCLFKIAMNILNMLFTGLFTVEMILKLIAFKPKGYFSDPWNVFDFLIVIGSIIDVIL
SETNHYFCDAWNTFDALIVVGSIVDIAITEVNPAEHTQCSPSMNAEENSRISITFFRLFR
VMRLVKLLSRGEGIRTLLWTFIKSFQALPYVALLIVMLFFIYAVIGMQVFGKIALNDTTE
INRNNNFQTFPQAVLLLFRCATGEAWQDIMLACMPGKKCAPESEPSNSTEGETPCGSSFA
VFYFISFYMLCAFLIINLFVAVIMDNFDYLTRDWSILGPHHLDEFKRIWAEYDPEAKGRI
KHLDVVTLLRRIQPPLGFGKLCPHRVACKRLVSMNMPLNSDGTVMFNATLFALVRTALRI
KTEGNLEQANEELRAIIKKIWKRTSMKLLDQVVPPAGDDEVTVGKFYATFLIQEYFRKFK
KRKEQGLVGKPSQRNALSLQAGLRTLHDIGPEIRRAISGDLTAEEELDKAMKEAVSAASE
DDIFRRAGGLFGNHVSYYQSDGRSAFPQTFTTQRPLHINKAGSSQGDTESPSHEKLVDST
FTPSSYSSTGSNANINNANNTALGRLPRPAGYPSTVSTVEGHGPPLSPAIRVQEVAWKLS
SNRERHVPMCEDLELRRDSGSAGTQAHCLLLRKANPSRCHSRESQAAMAGQEETSQDETY
EVKMNHDTEACSEPSLLSTEMLSYQDDENRQLTLPEEDKRDIRQSPKRGFLRSASLGRRA
SFHLECLKRQKDRGGDISQKTVLPLHLVHHQALAVAGLSPLLQRSHSPASFPRPFATPPA
TPGSRGWPPQPVPTLRLEGVESSEKLNSSFPSIHCGSWAETTPGGGGSSAARRVRPVSLM
VPSQAGAPGRQFHGSASSLVEAVLISEGLGQFAQDPKFIEVTTQELADACDMTIEEMESA
ADNILSGGAPQSPNGALLPFVNCRDAGQDRAGGEEDAGCVRARGRPSEEELQDSRVYVSS
L

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3D Structure

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AlphaFold

HIT2.0 ID

T77YFO

Drugs and Modes of Action

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Approved Drug(s)

[+] 1 Approved Drugs

RAUWOLFIA SERPENTINA ROOT

Drug Info

Approved

Discovery agent

[1]

Clinical Trial Drug(s)

[+] 1 Clinical Trial Drugs

ARC029

Drug Info

Phase 3

Alzheimer disease

[2]

Discontinued Drug(s)

[+] 3 Discontinued Drugs

R-56865

Drug Info

Terminated

Angina pectoris

[3]

SNAP-5089

Drug Info

Terminated

Heart arrhythmia

[4], [5]

TH-9229

Drug Info

Terminated

Reperfusion injury

[6]

Mode of Action

[+] 5 Modes of Action

Inhibitor

[+] 10 Inhibitor drugs

RAUWOLFIA SERPENTINA ROOT

Drug Info

[1]

ARC029

Drug Info

[7]

CGS-27830

Drug Info

[8]

NIGULDIPINE

Drug Info

[1]

R-56865

Drug Info

[9]

SNAP-5089

Drug Info

[10]

CORYNANTHEINE

Drug Info

[1]

CV-4093

Drug Info

[7]

MEBUDIPINE

Drug Info

[15]

PD-32577

Drug Info

[16]

Modulator

[+] 2 Modulator drugs

TH-9229

Drug Info

[11]

CPU-228

Drug Info

[13]

Blocker (channel blocker)

[+] 1 Blocker (channel blocker) drugs

(-)-(R)-efonidipine

Drug Info

[12]

Activator

[+] 3 Activator drugs

(-)-(S)-BayK8644

Drug Info

[13]

FPL64176

Drug Info

[14]

SZ(+)-(S)-202-791

Drug Info

[13]

Inhibitor (gating inhibitor)

[+] 3 Inhibitor (gating inhibitor) drugs

[3H](+)-cis-diltiazem

Drug Info

[17]

[3H](+)-isradipine

Drug Info

[18]

[3H](-)devapamil

Drug Info

[19]

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Co-Targets

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Co-Targets

Co-Targets Info

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Regulators

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Target-regulating microRNAs

Target-regulating microRNAs Info

Target Affiliated Biological Pathways		Top
KEGG Pathway	[+] 24 KEGG Pathways	+
1	MAPK signaling pathway
2	Calcium signaling pathway
3	cGMP-PKG signaling pathway
4	cAMP signaling pathway
5	Cardiac muscle contraction
6	Adrenergic signaling in cardiomyocytes
7	Vascular smooth muscle contraction
8	Circadian entrainment
9	Long-term potentiation
10	Retrograde endocannabinoid signaling
11	Glutamatergic synapse
12	Cholinergic synapse
13	Serotonergic synapse
14	GABAergic synapse
15	Dopaminergic synapse
16	Insulin secretion
17	GnRH signaling pathway
18	Oxytocin signaling pathway
19	Type II diabetes mellitus
20	Alzheimer's disease
21	Amphetamine addiction
22	Hypertrophic cardiomyopathy (HCM)
23	Arrhythmogenic right ventricular cardiomyopathy (ARVC)
24	Dilated cardiomyopathy
NetPath Pathway	[+] 1 NetPath Pathways	+
1	IL2 Signaling Pathway
Panther Pathway	[+] 7 Panther Pathways	+
1	Alzheimer disease-amyloid secretase pathway
2	Nicotinic acetylcholine receptor signaling pathway
3	5HT2 type receptor mediated signaling pathway
4	Beta1 adrenergic receptor signaling pathway
5	Beta2 adrenergic receptor signaling pathway
6	Oxytocin receptor mediated signaling pathway
7	Nicotine pharmacodynamics pathway
Pathwhiz Pathway	[+] 1 Pathwhiz Pathways	+
1	Muscle/Heart Contraction
Reactome	[+] 3 Reactome Pathways	+
1	Adrenaline,noradrenaline inhibits insulin secretion
2	NCAM1 interactions
3	Regulation of insulin secretion
WikiPathways	[+] 6 WikiPathways	+
1	Calcium Regulation in the Cardiac Cell
2	Arrhythmogenic Right Ventricular Cardiomyopathy
3	Alzheimers Disease
4	NCAM signaling for neurite out-growth
5	Integration of energy metabolism
6	Nicotine Activity on Chromaffin Cells

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

Alpha- and beta-adrenoceptors: from the gene to the clinic. 2. Structure-activity relationships and therapeutic applications. J Med Chem. 1995 Sep 15;38(19):3681-716.

REF 2

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800031727)

REF 3

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000253)

REF 4

URL: 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 5

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800006771)

REF 6

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800008159)

REF 7

Dihydropyrimidines: novel calcium antagonists with potent and long-lasting vasodilative and antihypertensive activity. J Med Chem. 1989 Oct;32(10):2399-406.

REF 8

CGS 27830, a potent nonpeptide endothelin receptor antagonist, Bioorg. Med. Chem. Lett. 3(10):2099-2104 (1993).

REF 9

Novel calcium antagonists with both calcium overload inhibition and antioxidant activity. 1. 2-(3, 5-di-tert-butyl-4-hydroxyphenyl)-3-(aminopropyl)... J Med Chem. 1998 Oct 22;41(22):4309-16.

REF 10

Design and synthesis of novel dihydropyridine alpha-1a antagonists. Bioorg Med Chem Lett. 1999 Oct 4;9(19):2843-8.

REF 11

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800008159)

REF 12

Identification of R(-)-isomer of efonidipine as a selective blocker of T-type Ca2+ channels. Br J Pharmacol. 2004 Dec;143(8):1050-7.

REF 13

REF 14

The calcium channel ligand FPL 64176 enhances L-type but inhibits N-type neuronal calcium currents. Neuropharmacology. 2003 Aug;45(2):281-92.

REF 15

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. Bioorg Med Chem. 2010 May 1;18(9):3147-58.

REF 16

Synthesis and biological activity of substituted bis-(4-hydroxyphenyl)methanes as N-type calcium channel blockers. Bioorg Med Chem Lett. 1999 Aug 16;9(16):2447-52.

REF 17

SR 33557, a novel calcium entry blocker. II. Interactions with 1,4-dihydropyridine, phenylalkylamine and benzothiazepine binding sites in rat heart sarcolemmal membranes. J Pharmacol Exp Ther. 1990 Nov;255(2):600-7.

REF 18

Isoform-specific regulation of mood behavior and pancreatic beta cell and cardiovascular function by L-type Ca 2+ channels. J Clin Invest. 2004 May;113(10):1430-9.

REF 19

Pharmacological, radioligand binding, and electrophysiological characteristics of FPL 64176, a novel nondihydropyridine Ca2+ channel activator, in cardiac and vascular preparations. Mol Pharmacol. 1991 Nov;40(5):734-41.

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