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. 

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 channel, voltage-dependent, T type, alpha 1I subunit 12
Mouse 24 1 2199 15 E1 Cacna1i calcium channel, voltage-dependent, alpha 1I subunit
Rat 24 1 2201 7q34 Cacna1i calcium channel, voltage-dependent, T type, alpha 1I subunit 8
Previous and Unofficial Names
CavT.3
α1I
Cav3.3
T-type
α1I
caVT.3
calcium channel, voltage-dependent, T type, alpha 1I subunit
calcium channel, voltage-dependent, alpha 1I subunit
low voltage-activated T-type calcium channel alpha-1 subunit (CACNA1I)
voltage-dependent T-type calcium channel subunit alpha-1I
voltage-dependent calcium channel
voltage-gated calcium channel subunit alpha Cav3.3
Database Links
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
GeneCards
GenitoUrinary Development Molecular Anatomy Project
HomoloGene
Human Protein Reference Database
InterPro
KEGG Gene
OMIM
PharmGKB Gene
PhosphoSitePlus
Protein Ontology (PRO)
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniGene Hs.
UniProtKB
Wikipedia
Functional Characteristics
Low voltage-activated, moderate inactivation
Ion Selectivity and Conductance
Species:  Human
Rank order:  Ca2+ [11.0 pS]
References:  12
Species:  Rat
Rank order:  Sr2+ = Ba2+ = Ca2+
References:  15-17
Voltage Dependence
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  -44.9 – -41.8 5.9 – 53.0 5 HEK 293 cells. Human
Inactivation  -72.0 – -71.5 68.0 – 127.0 5
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  -38.7 – -37.2 (median: -38.3) 5.0 – 45.0 13 HEK 293 cells. Human
Inactivation  -73.1 – -71.0 (median: -72.6) 66.0 – 111.0 13
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 - 12 HEK 293 cells. Human
Inactivation  -68.9 89.1 – 272.9 12
Comments  Ca2+ currents were measured with 2 mM Ca Cl2 The test potentials for the kinetics were -50mV (high values) and -10mV (low values).
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 Affinity Units Concentration range (M) Holding voltage (mV) Reference
pimozide Hs Antagonist 7.5 pIC50 - -100.0 14
pIC50 7.5 [14]
Holding voltage: -100.0 mV
anandamide Hs Antagonist 6.0 pIC50 - -80.0 3
pIC50 6.0 [3]
Holding voltage: -80.0 mV
mibefradil Hs Antagonist 5.8 pIC50 - -110.0 10
pIC50 5.8 (IC50 1.5x10-6 M) [10]
Holding voltage: -110.0 mV
Ni2+ Rn Antagonist 3.7 – 4.1 pIC50 - -90.0 9
pIC50 3.7 – 4.1 (IC50 2.16x10-4 – 8.7x10-5 M) [9]
Holding voltage: -90.0 mV
SB209712 Hs - - - - -
View species-specific channel blocker tables
Channel Blocker Comments
Block by Ni2+ is voltage dependent [9].

Tissue Distribution
Brain (cerebellum, occipital lobe, frontal lobe, amygdale, caudate nucleus, hippocampus > temporal lobe, putamen > substantia nigra, medulla)
Species:  Human
Technique:  Northern Blot
References:  12
Brain (olfactory bulb > hippocampus > piriform cortex, reticular thalamic nucleus > striatum, cerebellum).
Species:  Rat
Technique:  In situ hybridisation
References:  18
Soma and entire dendrite in cortical CA3, hippocampal and subicular neurons.
Species:  Rat
Technique:  Immunohistochemistry
References:  11
Functional Assays
Patch clamp (whole cell currents)
Species:  Rat
Tissue:  Native habenular neurons.
Response measured:  Electrophysiological measurement of ICa.
References:  6
Two-microelectrode voltage clamp.
Species:  Rat
Tissue:  Recombinant Cav3.3 transiently expressed in Xenopus oocytes.
Response measured:  Electrophysiological measurement of ICa.
References:  9
Patch Clamp (whole cell currents).
Species:  Human
Tissue:  Recombinant Cav3.3 stably expressed in HEK 239 cells.
Response measured:  Electrophysiological measurement of ICa.
References:  4
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:  20
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:  6-7
Low threshold Ca2+ spike that mediates burst firing of neurons.
Species:  Human
Tissue:  HEK-293 cells transiently expressing Cav3.3
References:  2
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
Role: 
Drugs: 
Side effects:  Rarely: GI distress, drowsiness, leukopenia.
Therapeutic use:  Absence epilepsy.
References:  4,19
Mutations not determined
Biologically Significant Variants
Type:  Splice variant
Species:  Human
Amino acids:  2188
Nucleotide accession: 
Protein accession: 
Type:  Splice variant
Species:  Human
Amino acids:  2223
Nucleotide accession: 
Protein accession: 
References:  12
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 [1,13].
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

1. 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]

2. 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]

3. 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]

4. 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]

5. 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]

6. 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]

7. 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]

8. 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]

9. 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]

10. 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]

11. 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]

12. 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]

13. 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]

14. 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]

15. Shcheglovitov AK, Boldyrev AI, Lyubanova OP, Shuba YM,. (2005) Peculiarities of selectivity of three subtypes of low-threshold T-type calcium channels. . Neurophysiology37 (4): 277-286.

16. Shcheglovitov AK, Boldyrev AI, Lyubanova OP, Shuba YM,. (2005) Peculiarities of selectivity of three subtypes of low-threshold T-type calcium channels. . Neurophysiology37 (4): 277-286.

17. Shcheglovitov AK, Boldyrev AI, Lyubanova OP, Shuba YM,. (2005) Peculiarities of selectivity of three subtypes of low-threshold T-type calcium channels. . Neurophysiology37 (4): 277-286.

18. 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]

19. Wallace SJ. (1986) Use of ethosuximide and valproate in the treatment of epilepsy. Neurologic clinics4 (3): 601-16. [PMID:3092003]

20. 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]

To cite this database page, please use the following:

William A. Catterall, Edward Perez-Reyes, Terrance P. Snutch, Joerg Striessnig.
Voltage-gated calcium channels: Cav3.3. Last modified on 13/02/2014. Accessed on 24/09/2014. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=537.

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