Nomenclature: Cav3.2

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 2353 16p13.3 CACNA1H calcium channel, voltage-dependent, T type, alpha 1H subunit 7
Mouse 24 1 2359 17 A3.3 Cacna1h calcium channel, voltage-dependent, T type, alpha 1H subunit
Rat 24 1 2359 10q12 Cacna1h calcium channel, voltage-dependent, T type, alpha 1H subunit 20
Previous and Unofficial Names
a1H
CavT.2
Cav3.2
T-type
α1H
calcium channel, voltage-dependent, T type, alpha 1H subunit
voltage-dependent T-type calcium channel subunit alpha-1H
voltage-gated calcium channel subunit alpha Cav3.2
alpha13.2
T-type Cav3.2
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
Orphanet Gene
PharmGKB Gene
PhosphoSitePlus
Protein Ontology (PRO)
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniGene Hs.
UniProtKB
Wikipedia
Functional Characteristics
Low voltage-activated, fast inactivation
Ion Selectivity and Conductance
Species:  Human
Rank order:  Ca2+ [9.1 pS] = Ba2+
References:  38
Species:  Rat
Rank order:  Sr2+ = Ba2+ = Ca2+
References:  26-28
Voltage Dependence
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  -47.4 2.0 – 7.0 21 Dorsal root ganglion nociceptive neurons. Rat
Inactivation  -70.8 25.0 – 75.0 21
Comments  Native currents, recorded in 10 BaCl2. Kinetics recorded during test pulses to -50 mV (high) and -10 mV (low).
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  -59.9 – -51.8 (median: -55.9) 1.6 – 8.4 36 HEK 293 cells. Human
Inactivation  -86.5 – -81.7 (median: -84.8) 12.9 – 32.6 36
Comments  Recombinant, recorded in 5 mM CaCl2. The range of V0.5 values result from epilepsy mutations, while the kinetics reflects voltage dependence; the high values were recorded during test potentials to -55 mV; the low at -15 mV.
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  -43.7 1.8 – 9.9 10 HEK 293 cells. Human
Inactivation  -78.8 15.0 – 28.0 10
Comments  Recombinant, recorded in 5 mM CaCl2. The range of kinetics reflects voltage dependence: the high values recorded during test potentials to -50mV; the low to -10mV.
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  -44.0 – -38.6 (median: -41.9) 2.0 – 10.0 40 HEK 293 cells. Human
Inactivation  -56.6 – -46.9 (median: -50.7) 20.0 – 120.0 40
Comments  Recombinant, recorded in 2 mM CaCl2. Range of V0.5 values result from splice variation, while kinetics reflects voltage dependence: high recorded during test potentials to -50 mV; low at -15 mV. Values of V0.5,inact are more positive than other estimates due to the use of a short prepulse (0.2s vs. typical 5-15s).
Gating inhibitors
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Affinity Units Concentration range (M) Holding voltage (mV) Reference
kurtoxin Rn Antagonist 7.3 – 7.6 pIC50 - -90.0 5,30
pIC50 7.3 – 7.6 [5,30]
Holding voltage: -90.0 mV
Gating Inhibitor Comments
Kurtoxin was selective for recombinant channels expressed in oocytes, but not for native T-currents in thalamocortical cells [5,30].
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 Rn Antagonist 7.3 pIC50 - -100.0 24
pIC50 7.3 [24]
Holding voltage: -100.0 mV
mibefradil Hs Antagonist 5.9 – 7.2 (median: 6.8) pIC50 - -110.0 – -80.0 17
pIC50 5.9 – 7.2 (median: 6.8) (IC50 1.1x10-6 – 6.9x10-8 (median: 1.4x10-7) M) [17]
Holding voltage: -110.0 – -80.0 mV
anandamide Hs Antagonist 6.5 pIC50 - -80.0 1
pIC50 6.5 [1]
Holding voltage: -80.0 mV
Ni2+ Hs Antagonist 4.9 – 5.2 pIC50 - -90.0 16
pIC50 4.9 – 5.2 (IC50 1.2x10-5 – 5.7x10-6 M) [16]
Holding voltage: -90.0 mV
SB209712 Hs - - - - -
View species-specific channel blocker tables
Channel Blocker Comments
Block produced by Ni2+ is voltage dependent [16].

For review of all known blockers see references [11,18].
Tissue Distribution
Kidney > liver > heart, brain.> lung, skeletal muscle, pancreas, placenta
Species:  Human
Technique:  Northern Blot
References:  7,38
Putamen > amygdala, caudate nucleus > frontal lobe, hippocampus, cerebellum, substantia nigra > thalamus > medulla, spinal cord, occipital lobe, temporal lobe.
Species:  Human
Technique:  Northern Blot
References:  31,38
Olfactory bulb, indusium griseum, hippocampus > pineal gland, sensory ganglia > pituitary gland > amygdala.
Species:  Rat
Technique:  In situ hybridisation
References:  32
Soma and proximal dendrites in hippocampus.
Species:  Rat
Technique:  Immunohistochemistry
References:  19
Adrenal glomerulosa.
Species:  Rat
Technique:  In situ hybridisation
References:  25
Functional Assays
Patch clamp electrophysiology.
Species:  Rat
Tissue:  Recombinant Cav3.2 stably expressed in Xenopus laevis oocytes
Response measured:  Electrophysiological measurement of ICa.
References:  23
Patch-clamp (whole cell currents).
Species:  Human
Tissue:  Recombinant Cav3.2 stably expressed in HEK 293 cells.
Response measured:  Electrophysiological measurement of ICa.
References:  9
Fluorometric imaging.
Species:  Human
Tissue:  Recombinant Cav3.2 stably expressed in HEK 293 cells
Response measured:  Fluorescence after loading dye such as Fluo-4.
References:  39
Physiological Functions
Nociception (peripheral processing of noxious signals).
Species:  Mouse
Tissue:  Dorsal root ganglion nociceptors.
References:  4
Aldosterone secretion from zona glomerulosa cells.
Species:  Rat
Tissue:  Adrenal gland
References:  25,35
Coronary function (relaxation of coronary arteries).
Species:  Mouse
Tissue:  Heart.
References:  2
Physiological Consequences of Altering Gene Expression
Absence of Cav3.2 expression leads to diminished responses to painful stimuli and constitutively constricted coronary arterioles.
Species:  Mouse
Tissue:  Dorsal root ganglion nociceptors, heart
Technique:  Knockout
References:  2,4
Phenotypes, Alleles and Disease Models Mouse data from MGI

Show »

Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Cacna1htm1Kcam Cacna1htm1Kcam/Cacna1htm1Kcam
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:1928842  MP:0004112 abnormal arteriole morphology PMID: 14631046 
Cacna1htm1Kcam Cacna1htm1Kcam/Cacna1htm1Kcam
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:1928842  MP:0001614 abnormal blood vessel morphology PMID: 14631046 
Cacna1htm1Kcam Cacna1htm1Kcam/Cacna1htm1Kcam
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:1928842  MP:0002127 abnormal cardiovascular system morphology PMID: 14631046 
Cacna1htm1Kcam Cacna1htm1Kcam/Cacna1htm1Kcam
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:1928842  MP:0003484 abnormal channel response PMID: 14631046 
Cacna1htm1Kcam Cacna1htm1Kcam/Cacna1htm1Kcam
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:1928842  MP:0000278 abnormal myocardial fiber morphology PMID: 14631046 
Cacna1htm1Kcam Cacna1htm1Kcam/Cacna1htm1Kcam
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:1928842  MP:0003141 cardiac fibrosis PMID: 14631046 
Cacna1htm1Kcam Cacna1htm1Kcam/Cacna1htm1Kcam
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:1928842  MP:0001265 decreased body size PMID: 14631046 
Cacna1htm1Kcam Cacna1htm1Kcam/Cacna1htm1Kcam
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:1928842  MP:0003025 increased vasoconstriction PMID: 14631046 
Clinically-Relevant Mutations and Pathophysiology
Disease:  Neuropathic pain
Role: 
Drugs: 
Side effects:  N/A
Therapeutic use:  Analgesia.
References:  8
Mutations not determined
Disease:  Absence epilepsy
OMIM:  611942
Role: 
Drugs: 
Side effects:  Rarely: GI distress, drowsiness, leukopenia.
Therapeutic use:  Absence epilepsy.
References:  6,37
Click column headers to sort
Type Species Molecular location Description Reference
Missense Human D1463N 3,36
Missense Human G848S 3,36
Missense Human V831M 3,36
Missense Human G784S 3,36
Missense Human G775D 12,14
Missense Human G773D 3,36
Missense Human A748V 3,36
Missense Human R744Q 3,36
Missense Human P648L 3,36
Missense Human P618L 12,14
Missense Human G499S 3,36
Missense Human A480T 12,14
Missense Human C456S 3,36
Missense Human E282K 3,36
Missense Human F161L 3,36
Truncation Human V621X 12
Disease:  Autistic spectrum disorder
OMIM:  209850
Orphanet:  106
References: 
Click column headers to sort
Type Species Molecular location Description Reference
Missense Human A1874V 31
Missense Human W962C 31
Missense Human R902W 31
Missense Human R212C 31
Disease:  Heart failure
Role: 
Drugs: 
Side effects:  No serious side effects reported.
Therapeutic use:  Antihypertensive.
References:  15,22,29
Mutations not determined
Disease:  Epilepsy, childhood absence, susceptibility to, 6
OMIM:  611942
Orphanet:  64280
References: 
Mutations not determined
Gene Expression and Pathophysiology
Increased Cav3.2 expression.
Tissue or cell type:  Thalamic reticular nucleus
Pathophysiology:  Genetic Absence Epilepsy Rat from Strasbourg (GAERS) model
Species:  Rat
Technique:  Various
References:  33-34
Biologically Significant Variant Comments
Multiple splice variants of Cav3.2 exist, particularly with alternative use of exon 25C and 26 which affects the III-IV linker, and which alter the voltage dependence of activation and inactivation as well as the kinetics of the protein [40].
General Comments
The precise role of the Cav3.2 channels in the human cardiovascular system has not been resolved. Although rodents express T-type currents in atrial and pacemaker cells, these have not been detected in man. Some antihypertensive drugs of the dihydropyridine class (e.g. efonidipine) may have a renoprotective effect due to block of T-currents and relaxation of glomerular efferent arterioles [13].

REFERENCES

1. 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]

2. Chen CC, Lamping KG, Nuno DW, Barresi R, Prouty SJ, Lavoie JL, Cribbs LL, England SK, Sigmund CD, Weiss RM, Williamson RA, Hill JA, Campbell KP. (2003) Abnormal coronary function in mice deficient in alpha1H T-type Ca2+ channels. Science302 (5649): 1416-8. [PMID:14631046]

3. Chen Y, Lu J, Pan H, Zhang Y, Wu H, Xu K, Liu X, Jiang Y, Bao X, Yao Z, Ding K, Lo WH, Qiang B, Chan P, Shen Y, Wu X. (2003) Association between genetic variation of CACNA1H and childhood absence epilepsy. Ann. Neurol.54 (2): 239-43. [PMID:12891677]

4. Choi S, Na HS, Kim J, Lee J, Lee S, Kim D, Park J, Chen CC, Campbell KP, Shin HS. (2007) Attenuated pain responses in mice lacking Ca(V)3.2 T-type channels. Genes Brain Behav.6 (5): 425-31. [PMID:16939637]

5. 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]

6. 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]

7. Cribbs LL, Lee JH, Yang J, Satin J, Zhang Y, Daud A, Barclay J, Williamson MP, Fox M, Rees M, Perez-Reyes E. (1998) Cloning and characterization of alpha1H from human heart, a member of the T-type Ca2+ channel gene family. Circ. Res.83 (1): 103-9. [PMID:9670923]

8. Dogrul A, Gardell LR, Ossipov MH, Tulunay FC, Lai J, Porreca F. (2003) Reversal of experimental neuropathic pain by T-type calcium channel blockers. Pain105 (1-2): 159-68. [PMID:14499432]

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. Heron SE, Phillips HA, Mulley JC, Mazarib A, Neufeld MY, Berkovic SF, Scheffer IE. (2004) Genetic variation of CACNA1H in idiopathic generalized epilepsy. Ann. Neurol.55 (4): 595-6. [PMID:15048902]

13. Kawabata M, Ogawa T, Han WH, Takabatake T. (1999) Renal effects of efonidipine hydrochloride, a new calcium antagonist, in spontaneously hypertensive rats with glomerular injury. Clin. Exp. Pharmacol. Physiol.26 (9): 674-9. [PMID:10499155]

14. Khosravani H, Bladen C, Parker DB, Snutch TP, McRory JE, Zamponi GW. (2005) Effects of Cav3.2 channel mutations linked to idiopathic generalized epilepsy. Ann. Neurol.57 (5): 745-9. [PMID:15852375]

15. Lalevée N, Rebsamen MC, Barrère-Lemaire S, Perrier E, Nargeot J, Bénitah JP, Rossier MF. (2005) Aldosterone increases T-type calcium channel expression and in vitro beating frequency in neonatal rat cardiomyocytes. Cardiovasc. Res.67 (2): 216-24. [PMID:15919070]

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. 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]

18. McGivern JG. (2006) Pharmacology and drug discovery for T-type calcium channels. CNS Neurol. Disord. Drug Targets5 (6): 587-603. [PMID:17168744]

19. 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]

20. McRory JE, Santi CM, Hamming KS, Mezeyova J, Sutton KG, Baillie DL, Stea A, Snutch TP. (2001) Molecular and functional characterization of a family of rat brain T-type calcium channels. J. Biol. Chem.276 (6): 3999-4011. [PMID:11073957]

21. Nelson MT, Joksovic PM, Perez-Reyes E, Todorovic SM. (2005) The endogenous redox agent L-cysteine induces T-type Ca2+ channel-dependent sensitization of a novel subpopulation of rat peripheral nociceptors. J. Neurosci.25 (38): 8766-75. [PMID:16177046]

22. Okayama S, Imagawa K, Naya N, Iwama H, Somekawa S, Kawata H, Horii M, Nakajima T, Uemura S, Saito Y. (2006) Blocking T-type Ca2+ channels with efonidipine decreased plasma aldosterone concentration in healthy volunteers. Hypertens. Res.29 (7): 493-7. [PMID:17044661]

23. Park JH, Choi JK, Lee E, Lee JK, Rhim H, Seo SH, Kim Y, Doddareddy MR, Pae AN, Kang J, Roh EJ. (2007) Lead discovery and optimization of T-type calcium channel blockers. Bioorg. Med. Chem.15 (3): 1409-19. [PMID:17150365]

24. 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]

25. Schrier AD, Wang H, Talley EM, Perez-Reyes E, Barrett PQ. (2001) alpha1H T-type Ca2+ channel is the predominant subtype expressed in bovine and rat zona glomerulosa. Am. J. Physiol., Cell Physiol.280 (2): C265-72. [PMID:11208520]

26. 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.

27. 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.

28. 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.

29. Shimizu M, Ogawa K, Sasaki H, Uehara Y, Otsuka Y, Okumura H, Kusaka M, Hasuda T, Yamada T, Mochizukienter S,. (2003) Effects of efonidipine, an L- and T-Type dual calcium channel blocker, on heart rate and blood pressure in patients with mild to severe hypertension: an uncontrolled, open-label pilot study. Current Therapeutic Research64 (9): 707-714.

30. 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]

31. Splawski I, Yoo DS, Stotz SC, Cherry A, Clapham DE, Keating MT. (2006) CACNA1H mutations in autism spectrum disorders. J. Biol. Chem.281 (31): 22085-91. [PMID:16754686]

32. 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]

33. 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]

34. Tsakiridou E, Bertollini L, de Curtis M, Avanzini G, Pape HC. (1995) Selective increase in T-type calcium conductance of reticular thalamic neurons in a rat model of absence epilepsy. J. Neurosci.15 (4): 3110-7. [PMID:7722649]

35. Uebele VN, Nuss CE, Renger JJ, Connolly TM. (2004) Role of voltage-gated calcium channels in potassium-stimulated aldosterone secretion from rat adrenal zona glomerulosa cells. J. Steroid Biochem. Mol. Biol.92 (3): 209-18. [PMID:15555914]

36. Vitko I, Chen Y, Arias JM, Shen Y, Wu XR, Perez-Reyes E. (2005) Functional characterization and neuronal modeling of the effects of childhood absence epilepsy variants of CACNA1H, a T-type calcium channel. J. Neurosci.25 (19): 4844-55. [PMID:15888660]

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

38. Williams ME, Washburn MS, Hans M, Urrutia A, Brust PF, Prodanovich P, Harpold MM, Stauderman KA. (1999) Structure and functional characterization of a novel human low-voltage activated calcium channel. J. Neurochem.72 (2): 791-9. [PMID:9930755]

39. 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]

40. Zhong X, Liu JR, Kyle JW, Hanck DA, Agnew WS. (2006) A profile of alternative RNA splicing and transcript variation of CACNA1H, a human T-channel gene candidate for idiopathic generalized epilepsies. Hum. Mol. Genet.15 (9): 1497-512. [PMID:16565161]

To cite this database page, please use the following:

William A. Catterall, Edward Perez-Reyes, Terrance P. Snutch, Joerg Striessnig.
Voltage-gated calcium channels: Cav3.2. Last modified on 21/03/2014. Accessed on 20/04/2014. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=536.

Contact us | Print | Back to top | Help
Copyright © 2014 IUPHAR