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Cav3.1

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
Phenotypes, Alleles and Disease Models
Clinically-Relevant Mutations and Pathophysiology
Gene Expression and Pathophysiology
Biologically Significant Variants
References
Gene and Protein Information
Species TM P Loops AA Chromosomal Location Gene Symbol Gene Name Reference
Human 24 1 2377 17q22 CACNA1G calcium channel, voltage-dependent, T type, alpha 1G subunit 19
Mouse 24 1 2295 11 D Cacna1g calcium channel, voltage-dependent, T type, alpha 1G subunit 13
Rat 24 1 2254 10q26-q31 Cacna1g calcium channel, voltage-dependent, T type, alpha 1G subunit 21
Previous and Unofficial Names
α1G
CavT.1
Cav3.1
T-type
α1G
NBR13
calcium channel, voltage-dependent, T type, alpha 1G subunit
voltage-dependent T-type calcium channel subunit alpha-1G
voltage-gated calcium channel subunit alpha Cav3.1
a1G
Cav3.1d
Database Links
ChEMBL Target 100100 (Hs), 18020 (Rn)
DrugBank Target 535 (Hs)
Ensembl ENSG00000006283 (Hs), ENSMUSG00000020866 (Mm), ENSRNOG00000002981 (Rn)
Entrez Gene 8913 (Hs), 12291 (Mm), 29717 (Rn)
GeneCards CACNA1G (Hs)
GenitoUrinary Development Molecular Anatomy Project Cacna1g (Mm)
HomoloGene 22544 (Hs)
Human Protein Reference Database 04961 (Hs)
InterPro O43497 (Hs), O54898 (Rn)
KEGG Gene hsa:8913 (Hs), mmu:12291 (Mm), rno:29717 (Rn)
OMIM 604065 (Hs)
PharmGKB Gene PA381 (Hs)
PhosphoSitePlus O43497 (Hs), Q5SUF7 (Mm)
Protein Ontology (PRO) PRO:000001972 (Hs)
RefSeq Nucleotide NM_938190 (Hs), NM_198379 (Hs), NM_198387 (Hs), NM_198378 (Hs), NM_009783 (Mm), NM_031601 (Rn)
RefSeq Protein NP_938190 (Hs), NP_938192 (Hs), NP_938201 (Hs), NP_938193 (Hs), NP_061496 (Hs), NP_033913 (Mm), NP_113789 (Rn)
TreeFam ENSG00000006283 (Hs), ENSMUSG00000020866 (Mm), ENSRNOG00000002981 (Rn)
UniGene Hs. 591169 (Hs)
UniProt O43497 (Hs), O54898 (Rn)
Wikipedia Cav3.1
Voltage-gated calcium channels
Search for 3D structures on the PDB
Search by keyword: Voltage-gated calcium channels Cav3.1 Search by accession number: O43497, O54898
Ion Selectivity and Conductance
Species:  Human
Rank order:  Sr2+ > Ca2+ > Ba2+ [7.3 pS]
References:  19
Species:  Rat
Rank order:  Ba2+ = Sr2+ = Ca2+
References:  23-25
Voltage Dependence
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  -63.0 2.0 – 8.0 5 Thalamocortical relay neuron. Rat
Inactivation  -83.5 20.0 – 50.0 5
Comments  Native currents were recorded in 3 mM CaCl2. The kinetics are voltage dependant with the higher values obtained at during test pulses to -60 mV, the lower to -10 mV.
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  -56.0 – -46.0 (median: -50.0) 1.0 – 7.0 7 HEK 293 cells. Human
Inactivation  -78.0 – -62.0 (median: -68.0) 15.0 – 40.0 7
Comments  Recombinant, recorded in 2 mM CaCl2. The range of V0.5 values result from splice variation, while the range of kinetics reflects voltage dependence: the high values were recorded during test potentials to -50 mV, the low at -15 mV.
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  -51.2 – -45.7 (median: -46.3) - 1 HEK 293 cells. Human
Inactivation  -80.6 – -65.0 (median: -71.1) 11.1 – 21.8 1
Comments  Recombinant, recorded in 2 mM CaCl2. The range of V0.5 values result from splice variation, while the kinetics reflect voltage dependence; the high values are recorded during test potentials to -40 mV; low to -10 mV.
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  -45.2 1.1 – 8.2 10 HEK 293 cells. Human
Inactivation  -76.9 16.0 – 62.0 10
Comments  Recombinant, recorded in 5 mM CaCl2. The range of kinetics reflects voltage-dependence; the high values recorded during test potentials to -50 mV; the low at -10 mV.
Gating inhibitors
Key to terms and symbols Click column headers to sort
Ligand Sp. Affinity Units Concentration range (M) Holding voltage (mV) Reference
kurtoxin Rn 7.3 – 7.8 pIC50 - -90.0 3,26
Gating Inhibitor Comments
Kurtoxin was selective for recombinant channels expressed in oocytes, but not for native T-currents in thalamocortical cells [3,26].
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 Rn 7.5 pIC50 - -100.0 22
mibefradil Hs 6.0 – 6.6 pIC50 - -110.0 – -100.0 16
(-)-(R)-efonidipine Rn 5.0 – 7.0 pIC50 - -100.0 – -60.0 8
anandamide Hs 5.4 pIC50 - -80.0 2
Ni2+ Rn 3.6 – 3.8 pIC50 - -90.0 14
View species-specific pore blocker tables
Pore Blocker Comments
Block by Ni2+ is voltage dependent [14].

For review of all known blockers see references [11,17].
Tissue Distribution
Brain > ovary > placenta.
Cerebellum > thalamus > neocortex > substantia nigra > medulla > striatum.
Species:  Human
Technique:  Northern Blot
References:  19
Basal forebrain, thalamus, cerebellum, inferior olive nucleus > olfactory bulb, amygdale > hypothalamus, neocortex, hippocampus, medulla > spinal cord.
Species:  Rat
Technique:  In situ hybridisation
References:  27
Cerebellum > neocortex > thalamus, amygdala, hippoampus > medulla > striatum.
Soma and dendrites.
Species:  Rat
Technique:  Immunohistochemistry
References:  6,18
Functional Assays
Two-microelectrode voltage clamp.
Species:  Rat
Tissue:  Xenopus laevis oocytes transiently expressing recombinant Cav3.1.
Response measured:  Electrophysiological measurement of ICa.
References:  8
Patch-clamp (whole cell currents).
Species:  Human
Tissue:  HEK 293 cells stably expressing recombinant Cav3.1.
Response measured:  Electrophysiological measurement of ICa.
References:  9
Voltage-clamp techniques.
Species:  Rat
Tissue:  Brain (native thalamocortical neurons).
Response measured:  Electrophysiological measurement of ICa.
References:  4
Fluorometric imaging.
Species:  Human
Tissue:  HEK 293 cells stably expressing recombinant Cav3.1
Response measured:  Fluorescence after loading with dye such as Fluo-4.
References:  30
Physiological Functions
Low threshold Ca2+ spike that mediates burst firing of neurons.
Species:  Mouse
Tissue:  Thalamocortical neurons.
References:  12
Phase 4 depolarisation of sinoatrial nodal cells.
Species:  Mouse
Tissue:  Heart
References:  15
Physiological Functions Comments
The above references are examples for each function. For further references see [20].
Phenotypes, Alleles and Disease Models Mouse data from MGI

Click here to show/hide data

Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Cacna1gtm1Hssh Cacna1gtm1Hssh/Cacna1gtm1Hssh
involves: 129S4/SvJae * C57BL/6J		 MGI:1201678  MP:0005402 abnormal action potential PMID: 11498049 
Cacna1gtm1.1Stl Cacna1gtm1.1Stl/Cacna1gtm1.1Stl
involves: C57BL/6		 MGI:1201678  MP:0005402 abnormal action potential PMID: 15677322 
Cacna1gtm1Hssh Cacna1gtm1Hssh/Cacna1gtm1Hssh
involves: 129S4/SvJae		 MGI:1201678  MP:0006141 abnormal atrioventricular node conduction PMID: 16690884 
Cacna1gtm1Hssh Cacna1gtm1Hssh/Cacna1gtm1Hssh
involves: 129S4/SvJae		 MGI:1201678  MP:0001544 abnormal cardiovascular system physiology PMID: 16690884 
Cacna1gtm1Hssh Cacna1gtm1Hssh/Cacna1gtm1Hssh
involves: 129S4/SvJae * C57BL/6J		 MGI:1201678  MP:0003633 abnormal nervous system physiology PMID: 11498049 
Cacna1gtm1.1Abp Cacna1gtm1.1Abp/Cacna1gtm1.1Abp
involves: C57BL/6		 MGI:1201678  MP:0003463 abnormal single cell response PMID: 19657020 
Cacna1gtm1Hssh Cacna1gtm1Hssh/Cacna1gtm1Hssh
involves: 129S4/SvJae		 MGI:1201678  MP:0006142 abnormal sinoatrial node conduction PMID: 16690884 
Cacna1gtm1.1Stl Cacna1gtm1.1Stl/Cacna1gtm1.1Stl
involves: C57BL/6		 MGI:1201678  MP:0001501 abnormal sleep pattern PMID: 15677322 
Cacna1gtm1Stl|Tg(Kcnc2-cre)K128Stl Cacna1gtm1Stl/Cacna1gtm1Stl,Tg(Kcnc2-cre)K128Stl/0
involves: C57BL/6		 MGI:1201678  MGI:3530534  MP:0001501 abnormal sleep pattern PMID: 15677322 
Cacna1gtm1Hssh Cacna1gtm1Hssh/Cacna1gtm1Hssh
involves: 129S4/SvJae * C57BL/6J		 MGI:1201678  MP:0008840 abnormal spike wave discharge PMID: 11498049 
Cacna1gtm1Hssh Cacna1gtm1Hssh/Cacna1gtm1Hssh
involves: 129S4/SvJae		 MGI:1201678  MP:0005333 decreased heart rate PMID: 16690884 
Cacna1gtm1Hssh Cacna1gtm1Hssh/Cacna1gtm1Hssh
involves: 129S4/SvJae * C57BL/6J		 MGI:1201678  MP:0002887 decreased susceptibility to pharmacologically induced seizures PMID: 11498049 
Cacna1gtm1Dgen Cacna1gtm1Dgen/Cacna1gtm1Dgen
involves: 129/Sv * C57BL/6		 MGI:1201678  MP:0001399 hyperactivity PMID: 19451696 
Cacna1gtm1.1Stl Cacna1gtm1.1Stl/Cacna1gtm1.1Stl
involves: C57BL/6		 MGI:1201678  MP:0001402 hypoactivity PMID: 15677322 
Cacna1gtm1.1Stl Cacna1gtm1.1Stl/Cacna1gtm1.1Stl
involves: C57BL/6		 MGI:1201678  MP:0002578 impaired ability to fire action potentials PMID: 15677322 
Cacna1gtm1.1Abp Cacna1gtm1.1Abp/Cacna1gtm1.1Abp
involves: C57BL/6 * CBA		 MGI:1201678  MP:0009747 impaired behavioral response to xenobiotic PMID: 17525593 
Cacna1gtm1Dgen Cacna1gtm1Dgen/Cacna1gtm1Dgen
involves: 129/Sv * C57BL/6		 MGI:1201678  MP:0005659 increased resistance to diet-induced obesity PMID: 19451696 
Cacna1gtm1Hssh Cacna1gtm1Hssh/Cacna1gtm1Hssh
involves: 129S4/SvJae		 MGI:1201678  MP:0003896 prolonged PR interval PMID: 16690884 
Clinically-Relevant Mutations and Pathophysiology
Disease:  Absence epilepsy.
Role:  Thalamic oscillation.
Drugs:  Ethosuximide.
Side effects:  Rarely: GI distres, drowsiness, leukopenia.
Therapeutic use:  Absence epilepsy.
References:  4,29
Mutations not determined
Gene Expression and Pathophysiology
Increased expression in mouse models of absence epilepsy.
Tissue or cell type:  Thalamic neurons.
Pathophysiology:  Absense epilepsy.
Species:  Mouse
Technique: 
References:  31
Increased expression in rat models of absence epilepsy.
Tissue or cell type:  Thalamic neurons.
Pathophysiology:  Absence epilepsy.
Species:  Rat
Technique: 
References:  28
Biologically Significant Variants
Nucleotide accession:  NM_938190 
Protein accession:  NP_938190 
Amino acids:  2171
Type:  Splice variant
Species:  Human
References:  19
This variant affects the insertion/deletion on exon 14, altering the sequence of II-III loop. The kinetics of activation and deactivation are changed.
Nucleotide accession:  NM_198378 
Protein accession:  NP_938192 
Amino acids:  2273
Type:  Splice variant
Species:  Human
References:  1,7
This variant alters the sequence of the III-IV loop (exons 25A and 26) altering the voltage dependance of activation and inactivation and kinetics.
Nucleotide accession:  NM_198387 
Protein accession:  NP_938201 
Amino acids:  2250
Type:  Splice variant
Species:  Human
References:  1,7
This variant alters the sequence of the III-IV loop (exons 25A and 26) altering the voltage dependance of activation and inactivation and kinetics.
Nucleotide accession:  NM_198379 
Protein accession:  NP_938193 
Amino acids:  2298
Type:  Splice variant
Species:  Human
References:  1,7

REFERENCES

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1. Chemin, J; Monteil, A; Bourinet, E; Nargeot, J; Lory, P. (2001) Alternatively spliced alpha(1G) (Ca(V)3.1) intracellular loops promote specific T-type Ca(2+) channel gating properties. Biophys. J., 80 (3): 1238-50. [PMID:11222288]

2. 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]

3. Chuang, RS; Jaffe, H; Cribbs, L; Perez-Reyes, E; Swartz, KJ. (1998) Inhibition of T-type voltage-gated calcium channels by a new scorpion toxin. Nat. Neurosci., 1 (8): 668-74. [PMID:10196582]

4. Coulter, DA; Huguenard, JR; Prince, DA. (1989) Characterization of ethosuximide reduction of low-threshold calcium current in thalamic neurons. Ann. Neurol., 25 (6): 582-93. [PMID:2545161]

5. Coulter, DA; Huguenard, JR; Prince, DA. (1989) Calcium currents in rat thalamocortical relay neurones: kinetic properties of the transient, low-threshold current. J. Physiol. (Lond.), 414: 587-604. [PMID:2607443]

6. Craig, PJ; Beattie, RE; Folly, EA; Banerjee, MD; Reeves, MB; Priestley, JV; Carney, SL; Sher, E; Perez-Reyes, E; Volsen, SG. (1999) Distribution of the voltage-dependent calcium channel alpha1G subunit mRNA and protein throughout the mature rat brain. Eur. J. Neurosci., 11 (8): 2949-64. [PMID:10457190]

7. Emerick, MC; Stein, R; Kunze, R; McNulty, MM; Regan, MR; Hanck, DA; Agnew, WS. (2006) Profiling the array of Ca(v)3.1 variants from the human T-type calcium channel gene CACNA1G: alternative structures, developmental expression, and biophysical variations. Proteins, 64 (2): 320-42. [PMID:16671074]

8. Furukawa, T; Miura, R; Honda, M; Kamiya, N; Mori, Y; Takeshita, S; Isshiki, T; Nukada, T. (2004) Identification of R(-)-isomer of efonidipine as a selective blocker of T-type Ca2+ channels. Br. J. Pharmacol., 143 (8): 1050-7. [PMID:15545287]

9. 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]

10. 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]

11. 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]

12. Kim, D; Song, I; Keum, S; Lee, T; Jeong, MJ; Kim, SS; McEnery, MW; Shin, HS. (2001) Lack of the burst firing of thalamocortical relay neurons and resistance to absence seizures in mice lacking alpha(1G) T-type Ca(2+) channels. Neuron, 31 (1): 35-45. [PMID:11498049]

13. Klugbauer, N; Marais, E; Lacinová, L; Hofmann, F. (1999) A T-type calcium channel from mouse brain. Pflugers Arch., 437 (5): 710-5. [PMID:10087148]

14. 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]

15. Mangoni, ME; Traboulsie, A; Leoni, AL; Couette, B; Marger, L; Le Quang, K; Kupfer, E; Cohen-Solal, A; Vilar, J; Shin, HS; Escande, D; Charpentier, F; Nargeot, J; Lory, P. (2006) Bradycardia and slowing of the atrioventricular conduction in mice lacking CaV3.1/alpha1G T-type calcium channels. Circ. Res., 98 (11): 1422-30. [PMID:16690884]

16. 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]

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

18. 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]

19. Monteil, A; Chemin, J; Bourinet, E; Mennessier, G; Lory, P; Nargeot, J. (2000) Molecular and functional properties of the human alpha(1G) subunit that forms T-type calcium channels. J. Biol. Chem., 275 (9): 6090-100. [PMID:10692398]

20. Perez-Reyes, E. (2003) Molecular physiology of low-voltage-activated t-type calcium channels. Physiol. Rev., 83 (1): 117-61. [PMID:12506128]

21. Perez-Reyes, E; Cribbs, LL; Daud, A; Lacerda, AE; Barclay, J; Williamson, MP; Fox, M; Rees, M; Lee, JH. (1998) Molecular characterization of a neuronal low-voltage-activated T-type calcium channel. Nature, 391 (6670): 896-900. [PMID:9495342]

22. 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]

23. 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.

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. Sidach, SS; Mintz, IM. (2002) Kurtoxin, a gating modifier of neuronal high- and low-threshold ca channels. J. Neurosci., 22 (6): 2023-34. [PMID:11896142]

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. Talley, EM; Solórzano, G; Depaulis, A; Perez-Reyes, E; Bayliss, DA. (2000) Low-voltage-activated calcium channel subunit expression in a genetic model of absence epilepsy in the rat. Brain Res. Mol. Brain Res., 75 (1): 159-65. [PMID:10648900]

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

30. 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]

31. Zhang, Y; Mori, M; Burgess, DL; Noebels, JL. (2002) Mutations in high-voltage-activated calcium channel genes stimulate low-voltage-activated currents in mouse thalamic relay neurons. J. Neurosci., 22 (15): 6362-71. [PMID:12151514]

To cite this database page, please use the following:

William A. Catterall, Edward Perez-Reyes, Terrance P. Snutch, Joerg Striessnig.
Voltage-gated calcium channels: Cav3.1. Last modified on 03/11/2011. Accessed on 22/05/2013. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=535.


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