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Cav3.3

Family: Voltage-gated calcium channels

Contents:
Gene and Protein Information
Previous and Unofficial Names
Database Links
Ion Selectivity and Conductance
Voltage Dependence
Gating Inhibitors
Pore Blockers
Tissue Distribution
Functional Assays
Physiological Functions
Physiological Consequences of Altering Gene Expression
Clinically-Relevant Mutations and Pathophysiology
Biologically Significant Variants
General Comments
References
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 100101 (Hs), 18081 (Rn)
DrugBank Target 15 (Hs)
Ensembl ENSG00000100346 (Hs), ENSMUSG00000022416 (Mm), ENSRNOG00000029914 (Rn)
Entrez Gene 8911 (Hs), 239556 (Mm), 56827 (Rn)
GeneCards CACNA1I (Hs)
GenitoUrinary Development Molecular Anatomy Project Cacna1i (Mm)
HomoloGene 69331 (Hs)
Human Protein Reference Database 10500 (Hs)
InterPro Q9P0X4 (Hs), Q9Z0Y8 (Rn)
KEGG Gene hsa:8911 (Hs), mmu:239556 (Mm), rno:56827 (Rn)
OMIM 608230 (Hs)
PharmGKB Gene PA26011 (Hs)
PhosphoSitePlus Q9P0X4 (Hs)
Protein Ontology (PRO) PRO:000001973 (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)
TreeFam ENSG00000100346 (Hs), ENSMUSG00000022416 (Mm), ENSRNOG00000029914 (Rn)
UniGene Hs. 125116 (Hs)
UniProt Q9P0X4 (Hs), Q9Z0Y8 (Rn)
Wikipedia Cav3.3
Voltage-gated calcium channels
Search for 3D structures on the PDB
Search by keyword: Voltage-gated calcium channels Cav3.3 Search by accession number: Q9Z0Y8, Q9P0X4
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.
Pore Blockers
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Affinity Units Concentration range (M) Holding voltage (mV) Reference
pimozide Hs 7.5 pIC50 - -100.0 14
anandamide Hs 6.0 pIC50 - -80.0 3
mibefradil Hs 5.8 pIC50 - -110.0 10
Ni2+ Rn 3.7 – 4.1 pIC50 - -90.0 9
View species-specific pore blocker tables
Pore 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:  Thalamic oscillation.
Drugs:  Ethosuximide
Side effects:  Rarely: GI distress, drowsiness, leukopenia.
Therapeutic use:  Absence epilepsy.
References:  4,19
Mutations not determined
Biologically Significant Variants
Nucleotide accession:  NM_001003406 
Protein accession:  NP_001003406 
Amino acids:  2188
Type:  Splice variant
Species:  Human
References: 
Nucleotide accession:  NM_021096 
Protein accession:  NP_066919 
Amino acids:  2223
Type:  Splice variant
Species:  Human
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

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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. . Neurophysiology, 37 (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. . Neurophysiology, 37 (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. . Neurophysiology, 37 (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 clinics, 4 (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 03/11/2011. Accessed on 19/06/2013. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=537.


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