Ca<sub>v</sub>3.3 | Voltage-gated calcium channels | IUPHAR/BPS Guide to PHARMACOLOGY

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Cav3.3

Target not currently curated in GtoImmuPdb

Target id: 537

Nomenclature: Cav3.3

Family: Voltage-gated calcium channels

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

Contents:

Gene and Protein Information
Species TM P Loops AA Chromosomal Location Gene Symbol Gene Name Reference
Human 24 1 2223 22q13.1 CACNA1I calcium voltage-gated channel subunit alpha1 I 21
Mouse 24 1 2199 15 E1 Cacna1i calcium channel, voltage-dependent, alpha 1I subunit
Rat 24 1 2201 7q34 Cacna1i calcium voltage-gated channel subunit alpha1 I 15
Previous and Unofficial Names
α1I | CavT.3 | low voltage-activated T-type calcium channel alpha-1 subunit (CACNA1I) | alpha-1I | calcium channel
Database Links
ChEMBL Target CHEMBL5558 (Hs)
DrugBank Target Q9P0X4 (Hs)
Ensembl Gene ENSG00000100346 (Hs), ENSMUSG00000022416 (Mm), ENSRNOG00000029914 (Rn)
Entrez Gene 8911 (Hs), 239556 (Mm), 56827 (Rn)
Human Protein Atlas ENSG00000100346 (Hs)
KEGG Gene hsa:8911 (Hs), mmu:239556 (Mm), rno:56827 (Rn)
OMIM 608230 (Hs)
RefSeq Nucleotide NM_001003406 (Hs), NM_021096 (Hs), NM_001044308 (Mm), NM_020084 (Rn)
RefSeq Protein NP_066919 (Hs), NP_001003406 (Hs), NP_001037773 (Mm), NP_064469 (Rn)
UniProtKB Q9P0X4 (Hs), Q9Z0Y8 (Rn)
Wikipedia CACNA1I (Hs)
Functional Characteristics
T-type calcium current: Low voltage-activated, moderate voltage-dependent inactivation
Ion Selectivity and Conductance
Species:  Human
Rank order:  Ca2+ [11.0 pS]
References:  21
Species:  Rat
Rank order:  Sr2+ = Ba2+ = Ca2+
References:  24-26
Voltage Dependence
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  -44.9 – -41.8 5.9 – 53.0 9 HEK 293 cells. Human
Inactivation  -72.0 – -71.5 68.0 – 127.0 9
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  -38.7 – -37.2 (median: -38.3) 5.0 – 45.0 22 HEK 293 cells. Human
Inactivation  -73.1 – -71.0 (median: -72.6) 66.0 – 111.0 22
Comments  Ca2+ currents were measured with 5 mM CaCl2. Test potential for the channels kinetics were -40 mV (high values) and 0 mV (low values). Significant differences in kinetics of splice variants were found.
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  -40.6 - 21 HEK 293 cells. Human
Inactivation  -68.9 89.1 – 272.9 21
Comments  Ca2+ currents were measured with 2 mM Ca Cl2 The test potentials for the kinetics were -50mV (high values) and -10mV (low values).

Download all structure-activity data for this target as a CSV file

Gating Inhibitor Comments
Kurtoxin not tested on Cav3.3.
Channel Blockers
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Concentration range (M) Holding voltage (mV) Reference
pimozide Hs Antagonist 7.5 pIC50 - -100.0 23
⤷ pIC50 7.5 [23]
Holding voltage: -100.0 mV
TTA-A2 Hs Pore blocker 7.5 pIC50 - -75.0 6
⤷ pIC50 7.5 voltage-dependent [6]
Holding voltage: -75.0 mV
Z944 Hs Pore blocker 7.0 pIC50 - -75.0 28
⤷ pIC50 7.0 voltage-dependent [28]
Holding voltage: -75.0 mV
TTA-P2 Rn Pore blocker 7.0 pIC50 - -90.0 5
⤷ pIC50 7.0 [5]
Holding voltage: -90.0 mV
ML218 Hs Pore blocker 6.5 pIC50 - -90.0 30
⤷ pIC50 6.5 [30]
Holding voltage: -90.0 mV
anandamide Hs Antagonist 6.0 pIC50 - -80.0 4
⤷ pIC50 6.0 [4]
Holding voltage: -80.0 mV
mibefradil Hs Antagonist 5.8 pIC50 - -110.0 18
⤷ pIC50 5.8 (IC50 1.5x10-6 M) [18]
Holding voltage: -110.0 mV
3β-OH Rn Antagonist 5.7 pIC50 - - 1
⤷ pIC50 5.7 (IC50 2x10-6 M) [1]
Description: Inhibition of currents via native Cav3.3 currents in rat reticular thalamic nucleus.
ABT-639 Hs Pore blocker 5.0 pIC50 - -110.0 12
⤷ pIC50 5.0 [12]
Holding voltage: -110.0 mV
Ni2+ Rn Antagonist 3.7 – 4.1 pIC50 - -90.0 16
⤷ pIC50 3.7 – 4.1 (IC50 2.16x10-4 – 8.7x10-5 M) [16]
Holding voltage: -90.0 mV
View species-specific channel blocker tables
Channel Blocker Comments
Block by Ni2+ is voltage dependent [16]. For review of all known blockers see references [7,10,19,30]. ML218 was developed by NIH’s Molecular Libraries Production Center and is freely available without intellectual property restrictions [30].
Tissue Distribution
Brain (cerebellum, occipital lobe, frontal lobe, amygdale, caudate nucleus, hippocampus > temporal lobe, putamen > substantia nigra, medulla)
Species:  Human
Technique:  Northern Blot
References:  21
Isocortex, olfactory > striatum > cortical subplate, hippocampus > thalamus, hypothalamus, pallidum, midbrain, medulla.
Species:  Mouse
Technique:  In situ hybridisation
References:  17
Brain (olfactory bulb > hippocampus > piriform cortex, reticular thalamic nucleus > striatum, cerebellum).
Species:  Rat
Technique:  In situ hybridisation
References:  27
Soma and entire dendrite in cortical CA3, hippocampal and subicular neurons.
Species:  Rat
Technique:  Immunohistochemistry
References:  20
Functional Assays
Patch clamp (whole cell currents)
Species:  Rat
Tissue:  Native habenular neurons.
Response measured:  Electrophysiological measurement of ICa.
References:  11
Fluorometric imaging.
Species:  Human
Tissue:  Recombinant Cav3.3 stably expressed in HEK 239 cells.
Response measured:  Fluorescence after loading dye such as Fluo-4.
References:  31
Two-microelectrode voltage clamp.
Species:  Rat
Tissue:  Recombinant Cav3.3 transiently expressed in Xenopus oocytes.
Response measured:  Electrophysiological measurement of ICa.
References:  16
Patch Clamp (whole cell currents).
Species:  Human
Tissue:  Recombinant Cav3.3 stably expressed in HEK 239 cells.
Response measured:  Electrophysiological measurement of ICa.
References:  8
Physiological Functions
Low threshold Ca2+ spike that mediates burst firing of neurons.
Species:  Rat
Tissue:  Lateral habenula neurons and HEK-293 cells stably expressing Cav3.3.
References:  11,14
Low threshold Ca2+ spike that mediates burst firing of neurons.
Species:  Human
Tissue:  HEK-293 cells transiently expressing Cav3.3
References:  3
Physiological Consequences of Altering Gene Expression Comments
Results from transgenic Cav3.3 -/- mice have not been reported.
Clinically-Relevant Mutations and Pathophysiology
Disease:  Absence epilepsy
Synonyms: early onset absence epilepsy [Disease Ontology: DOID:0050708]
Disease Ontology: DOID:0050708
Role:  Thalamic oscillation.
Drugs:  Ethosuximide
Side effects:  Rarely: GI distress, drowsiness, leukopenia.
Therapeutic use:  Absence epilepsy.
Comments:  Mutation frequency not determined
References:  8,13,29
Biologically Significant Variants
Type:  Splice variant
Species:  Human
Amino acids:  2188
Nucleotide accession:  NM_001003406
Protein accession:  NP_001003406
Type:  Splice variant
Species:  Human
Amino acids:  2223
Nucleotide accession:  NM_021096
Protein accession:  NP_066919
References:  21
Biologically Significant Variant Comments
The rat gene contains additional sites of splicing. Variants which alter the I-II loop (exon 9) or the sequence of the carboxy terminus (exon 33) affect the kinetics of activation, inactivation and deinactivation [2,22].
General Comments
The recombinant channels show much slower kinetics, and a larger window current range than other Cav3.x channels, suggesting it could trigger longer lasting Ca2+ spikes. Consistent with this hypothesis, its mRNA is expressed in neurons capable of long lasting bursts (inferior olive and habenula).

References

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1. Atluri N, Joksimovic SM, Oklopcic A, Milanovic D, Klawitter J, Eggan P, Krishnan K, Covey DF, Todorovic SM, Jevtovic-Todorovic V. (2018) A neurosteroid analogue with T-type calcium channel blocking properties is an effective hypnotic, but is not harmful to neonatal rat brain. Br J Anaesth, 120 (4): 768-778. [PMID:29576117]

2. Chemin J, Monteil A, Dubel S, Nargeot J, Lory P. (2001) The alpha1I T-type calcium channel exhibits faster gating properties when overexpressed in neuroblastoma/glioma NG 108-15 cells. Eur. J. Neurosci., 14 (10): 1678-86. [PMID:11860462]

3. Chemin J, Monteil A, Perez-Reyes E, Bourinet E, Nargeot J, Lory P. (2002) Specific contribution of human T-type calcium channel isotypes (alpha(1G), alpha(1H) and alpha(1I)) to neuronal excitability. J. Physiol. (Lond.), 540 (Pt 1): 3-14. [PMID:11927664]

4. Chemin J, Monteil A, Perez-Reyes E, Nargeot J, Lory P. (2001) Direct inhibition of T-type calcium channels by the endogenous cannabinoid anandamide. EMBO J., 20 (24): 7033-40. [PMID:11742980]

5. Choe W, Messinger RB, Leach E, Eckle VS, Obradovic A, Salajegheh R, Jevtovic-Todorovic V, Todorovic SM. (2011) TTA-P2 is a potent and selective blocker of T-type calcium channels in rat sensory neurons and a novel antinociceptive agent. Mol. Pharmacol., 80 (5): 900-10. [PMID:21821734]

6. Francois A, Kerckhove N, Meleine M, Alloui A, Barrere C, Gelot A, Uebele VN, Renger JJ, Eschalier A, Ardid D et al.. (2013) State-dependent properties of a new T-type calcium channel blocker enhance Ca(V)3.2 selectivity and support analgesic effects. Pain, 154 (2): 283-93. [PMID:23257507]

7. Giordanetto F, Knerr L, Wållberg A. (2011) T-type calcium channels inhibitors: a patent review. Expert Opin Ther Pat, 21 (1): 85-101. [PMID:21087200]

8. Gomora JC, Daud AN, Weiergräber M, Perez-Reyes E. (2001) Block of cloned human T-type calcium channels by succinimide antiepileptic drugs. Mol. Pharmacol., 60 (5): 1121-32. [PMID:11641441]

9. Gomora JC, Murbartián J, Arias JM, Lee JH, Perez-Reyes E. (2002) Cloning and expression of the human T-type channel Ca(v)3.3: insights into prepulse facilitation. Biophys. J., 83 (1): 229-41. [PMID:12080115]

10. Heady TN, Gomora JC, Macdonald TL, Perez-Reyes E. (2001) Molecular pharmacology of T-type Ca2+ channels. Jpn. J. Pharmacol., 85 (4): 339-50. [PMID:11388636]

11. Huguenard JR, Gutnick MJ, Prince DA. (1993) Transient Ca2+ currents in neurons isolated from rat lateral habenula. J. Neurophysiol., 70 (1): 158-66. [PMID:8395572]

12. Jarvis MF, Scott VE, McGaraughty S, Chu KL, Xu J, Niforatos W, Milicic I, Joshi S, Zhang Q, Xia Z. (2014) A peripherally acting, selective T-type calcium channel blocker, ABT-639, effectively reduces nociceptive and neuropathic pain in rats. Biochem. Pharmacol., 89 (4): 536-44. [PMID:24726441]

13. Klassen T, Davis C, Goldman A, Burgess D, Chen T, Wheeler D, McPherson J, Bourquin T, Lewis L, Villasana D et al.. (2011) Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy. Cell, 145 (7): 1036-48. [PMID:21703448]

14. Kozlov AS, McKenna F, Lee JH, Cribbs LL, Perez-Reyes E, Feltz A, Lambert RC. (1999) Distinct kinetics of cloned T-type Ca2 + channels lead to differential Ca2 + entry and frequency-dependence during mock action potentials. Eur. J. Neurosci., 11 (12): 4149-58. [PMID:10594640]

15. Lee JH, Daud AN, Cribbs LL, Lacerda AE, Pereverzev A, Klöckner U, Schneider T, Perez-Reyes E. (1999) Cloning and expression of a novel member of the low voltage-activated T-type calcium channel family. J. Neurosci., 19 (6): 1912-21. [PMID:10066244]

16. Lee JH, Gomora JC, Cribbs LL, Perez-Reyes E. (1999) Nickel block of three cloned T-type calcium channels: low concentrations selectively block alpha1H. Biophys. J., 77 (6): 3034-42. [PMID:10585925]

17. Lein ES, Hawrylycz MJ, Ao N, Ayres M, Bensinger A, Bernard A, Boe AF, Boguski MS, Brockway KS, Byrnes EJ et al.. (2007) Genome-wide atlas of gene expression in the adult mouse brain. Nature, 445 (7124): 168-76. [PMID:17151600]

18. Martin RL, Lee JH, Cribbs LL, Perez-Reyes E, Hanck DA. (2000) Mibefradil block of cloned T-type calcium channels. J. Pharmacol. Exp. Ther., 295 (1): 302-8. [PMID:10991994]

19. McGivern JG. (2006) Pharmacology and drug discovery for T-type calcium channels. CNS Neurol Disord Drug Targets, 5 (6): 587-603. [PMID:17168744]

20. McKay BE, McRory JE, Molineux ML, Hamid J, Snutch TP, Zamponi GW, Turner RW. (2006) Ca(V)3 T-type calcium channel isoforms differentially distribute to somatic and dendritic compartments in rat central neurons. Eur. J. Neurosci., 24 (9): 2581-94. [PMID:17100846]

21. Monteil A, Chemin J, Leuranguer V, Altier C, Mennessier G, Bourinet E, Lory P, Nargeot J. (2000) Specific properties of T-type calcium channels generated by the human alpha 1I subunit. J. Biol. Chem., 275 (22): 16530-5. [PMID:10749850]

22. Murbartián J, Arias JM, Perez-Reyes E. (2004) Functional impact of alternative splicing of human T-type Cav3.3 calcium channels. J. Neurophysiol., 92 (6): 3399-407. [PMID:15254077]

23. Santi CM, Cayabyab FS, Sutton KG, McRory JE, Mezeyova J, Hamming KS, Parker D, Stea A, Snutch TP. (2002) Differential inhibition of T-type calcium channels by neuroleptics. J. Neurosci., 22 (2): 396-403. [PMID:11784784]

24. Shcheglovitov AK, Boldyrev AI, Lyubanova OP, Shuba YM,. (2005) Peculiarities of selectivity of three subtypes of low-threshold T-type calcium channels. Neurophysiology, 37 (4): 277-286.

25. Shcheglovitov AK, Boldyrev AI, Lyubanova OP, Shuba YM,. (2005) Peculiarities of selectivity of three subtypes of low-threshold T-type calcium channels. Neurophysiology, 37 (4): 277-286.

26. Shcheglovitov AK, Boldyrev AI, Lyubanova OP, Shuba YM,. (2005) Peculiarities of selectivity of three subtypes of low-threshold T-type calcium channels. Neurophysiology, 37 (4): 277-286.

27. Talley EM, Cribbs LL, Lee JH, Daud A, Perez-Reyes E, Bayliss DA. (1999) Differential distribution of three members of a gene family encoding low voltage-activated (T-type) calcium channels. J. Neurosci., 19 (6): 1895-911. [PMID:10066243]

28. Tringham E, Powell KL, Cain SM, Kuplast K, Mezeyova J, Weerapura M, Eduljee C, Jiang X, Smith P, Morrison JL et al.. (2012) T-type calcium channel blockers that attenuate thalamic burst firing and suppress absence seizures. Sci Transl Med, 4 (121): 121ra19. [PMID:22344687]

29. Wallace SJ. (1986) Use of ethosuximide and valproate in the treatment of epilepsy. Neurologic clinics, 4 (3): 601-16. [PMID:3092003]

30. Xiang Z, Thompson AD, Brogan JT, Schulte ML, Melancon BJ, Mi D, Lewis LM, Zou B, Yang L, Morrison R et al.. (2011) The 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, 2 (12): 730-742. [PMID:22368764]

31. Xie X, Van Deusen AL, Vitko I, Babu DA, Davies LA, Huynh N, Cheng H, Yang N, Barrett PQ, Perez-Reyes E. (2007) Validation of high throughput screening assays against three subtypes of Ca(v)3 T-type channels using molecular and pharmacologic approaches. Assay Drug Dev Technol, 5 (2): 191-203. [PMID:17477828]

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