Cav2.3

Description: calcium channel, voltage-dependent, R type, alpha 1E subunit
Gene: Cacna1e
Alias: cacna1e, cav2.3, ca2.3

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Introduction

The R type calcium channel, also know as a1E or Cav2.3, is an HVA calcium channel found in neurons. R-type Ca2+ currents have been pharmacologically defined by their resistance to blockers of L-type, N-type, and P/Q-type Ca2+ channels [512] and by their sensitivity to SNX-482, a peptide component of spider venom [513].

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Gene

GeneID: 54234 Cacna1e calcium channel, voltage-dependent, R type, alpha 1E subunit [ Rattus norvegicus ]

Species	NCBI gene ID	Chromosome	Position
Human	777	1	490385
Mouse	12290	1	493822
Rat	54234	13	488784

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Transcript

Species	NCBI accession	Length (nt)
Human	NM_001205293.3	16420
Mouse	NM_009782.3	12697
Rat	NM_019294.3	7367

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Protein Isoforms

Species	Uniprot ID	Length (aa)
Human	Q15878	2313
Mouse	Q61290	2272
Rat	Q07652	2222

Isoforms

Transcript

Length (nt)

Protein

Length (aa)

Variant

Isoform

Known

NM_001205293.3

16420

NP_001192222.1

2313

transcript variant 1

isoform 1

NM_000721.4

16291

NP_000712.2

2270

transcript variant 3

isoform 3

NM_001205294.2

16234

NP_001192223.1

2251

transcript variant 2

isoform 2

Predicted

XM_017002244.2

17066

XP_016857733.1

2458

transcript variant X2

isoform X2

XM_017002243.2

17066

XP_016857732.1

2458

transcript variant X1

isoform X1

XM_017002249.2

16937

XP_016857738.1

2415

transcript variant X8

isoform X8

XM_017002248.2

17000

XP_016857737.1

2436

transcript variant X6

isoform X6

XM_017002246.2

17054

XP_016857735.1

2454

transcript variant X4

isoform X4

XM_017002245.2

17054

XP_016857734.1

2454

transcript variant X3

isoform X3

XM_017002247.2

17009

XP_016857736.1

2439

transcript variant X5

isoform X5

XM_017002250.2

16880

XP_016857739.1

2396

transcript variant X9

isoform X9

XM_047429979.1

16997

XP_047285935.1

2435

transcript variant X7

isoform X7

XM_047429980.1

6561

XP_047285936.1

1897

transcript variant X11

isoform X10

XM_017002251.1

16710

XP_016857740.1

2458

transcript variant X10

isoform X1

XM_054338635.1

17057

XP_054194610.1

2458

transcript variant X2

isoform X2

XM_054338634.1

17057

XP_054194609.1

2458

transcript variant X1

isoform X1

XM_054338639.1

16991

XP_054194614.1

2436

transcript variant X6

isoform X6

XM_054338637.1

17045

XP_054194612.1

2454

transcript variant X4

isoform X4

XM_054338636.1

17045

XP_054194611.1

2454

transcript variant X3

isoform X3

XM_054338638.1

17000

XP_054194613.1

2439

transcript variant X5

isoform X5

XM_054338640.1

16988

XP_054194615.1

2435

transcript variant X7

isoform X7

XM_054338644.1

9125

XP_054194619.1

1897

transcript variant X11

isoform X10

XM_054338641.1

16927

XP_054194616.1

2415

transcript variant X8

isoform X8

XM_054338642.1

16870

XP_054194617.1

2396

transcript variant X9

isoform X9

XM_054338643.1

16714

XP_054194618.1

2458

transcript variant X10

isoform X1

Known

NM_009782.3

12697

NP_033912.2

2273

Predicted

XM_030243929.1

15080

XP_030099789.1

2466

transcript variant X4

isoform X1

XM_017312578.3

15583

XP_017168067.1

2466

transcript variant X1

isoform X1

XM_017312848.1

15130

XP_017168337.1

2320

transcript variant X18

isoform X14

XM_017312712.1

15491

XP_017168201.1

2436

transcript variant X11

isoform X8

XM_017312660.1

15524

XP_017168149.1

2447

transcript variant X9

isoform X6

XM_017312628.1

15569

XP_017168117.1

2462

transcript variant X7

isoform X4

XM_017312642.1

15569

XP_017168131.1

2462

transcript variant X8

isoform X5

XM_017312619.1

15569

XP_017168108.1

2462

transcript variant X6

isoform X3

XM_017312730.1

15452

XP_017168219.1

2423

transcript variant X12

isoform X9

XM_017312613.1

15581

XP_017168102.1

2466

transcript variant X5

isoform X2

XM_030243926.1

15657

XP_030099786.1

2466

transcript variant X3

isoform X1

XM_011247909.4

15498

XP_011246211.1

2466

transcript variant X2

isoform X1

XM_011247916.4

51280

XP_011246218.1

2320

transcript variant X17

isoform X14

XM_030244154.2

52101

XP_030100014.1

2271

transcript variant X19

isoform X15

XM_017312745.2

12909

XP_017168234.1

2419

transcript variant X13

isoform X10

XM_017312824.2

10550

XP_017168313.1

2400

transcript variant X16

isoform X13

XM_017312766.2

10607

XP_017168255.1

2419

transcript variant X14

isoform X11

XM_017312795.2

7796

XP_017168284.1

2400

transcript variant X15

isoform X12

XM_017312682.2

7925

XP_017168171.1

2443

transcript variant X10

isoform X7

XM_036155941.1

7618

XP_036011834.1

2129

transcript variant X20

isoform X16

XM_006529105.5

6396

XP_006529168.1

1904

transcript variant X21

isoform X17

Known

NM_019294.3

7367

NP_062167.3

2296

Predicted

XM_039091008.1

15394

XP_038946936.1

2465

transcript variant X2

isoform X1

XM_039091012.1

15607

XP_038946940.1

2461

transcript variant X7

isoform X5

XM_039091011.1

15606

XP_038946939.1

2461

transcript variant X6

isoform X4

XM_039091010.1

15618

XP_038946938.1

2465

transcript variant X4

isoform X2

XM_039091013.1

15560

XP_038946941.1

2446

transcript variant X8

isoform X6

XM_039091007.1

15617

XP_038946935.1

2465

transcript variant X1

isoform X1

XM_039091015.1

15526

XP_038946943.1

2435

transcript variant X10

isoform X8

XM_039091016.1

15487

XP_038946944.1

2422

transcript variant X11

isoform X9

XM_039091009.1

15163

XP_038946937.1

2465

transcript variant X3

isoform X1

XM_039091017.1

14894

XP_038946945.1

2319

transcript variant X15

isoform X13

XM_017598911.2

8287

XP_017454400.1

2442

transcript variant X9

isoform X7

XM_017598913.2

8060

XP_017454402.1

2418

transcript variant X12

isoform X10

XM_017598915.2

7689

XP_017454404.1

2399

transcript variant X14

isoform X12

XM_017598908.2

7875

XP_017454397.1

2461

transcript variant X5

isoform X3

XM_017598914.2

7688

XP_017454403.1

2399

transcript variant X13

isoform X11

XM_039091018.1

8076

XP_038946946.1

1965

transcript variant X16

isoform X14

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Post-Translational Modifications

PTM

Position

Type

Modified residue

Phosphoserine

Modified residue

Phosphoserine

Modified residue

427

Phosphoserine

Modified residue

440

Phosphothreonine

Modified residue

736

Phosphoserine

Modified residue

745

Phosphoserine

Modified residue

793

Phosphoserine

Modified residue

815

Phosphoserine

Modified residue

855

Phosphoserine

Modified residue

947

Phosphoserine

Modified residue

1097

Phosphoserine

Modified residue

2094

Phosphoserine

Modified residue

2113

Phosphoserine

Glycosylation

254

N-linked (GlcNAc...) asparagine

Glycosylation

1566

N-linked (GlcNAc...) asparagine

Glycosylation

1571

N-linked (GlcNAc...) asparagine

Modified residue

Phosphoserine

Modified residue

Phosphoserine

Modified residue

428

Phosphoserine

Modified residue

441

Phosphothreonine

Modified residue

737

Phosphoserine

Modified residue

746

Phosphoserine

Modified residue

794

Phosphoserine

Modified residue

816

Phosphoserine

Modified residue

856

Phosphoserine

Modified residue

948

Phosphoserine

Modified residue

1099

Phosphoserine

Modified residue

2054

Phosphoserine

Modified residue

2073

Phosphoserine

Glycosylation

255

N-linked (GlcNAc...) asparagine

Glycosylation

1569

N-linked (GlcNAc...) asparagine

Glycosylation

1692

N-linked (GlcNAc...) asparagine

Modified residue

378

Phosphoserine

Modified residue

391

Phosphothreonine

Modified residue

687

Phosphoserine

Modified residue

696

Phosphoserine

Modified residue

744

Phosphoserine

Modified residue

766

Phosphoserine

Modified residue

806

Phosphoserine

Modified residue

898

Phosphoserine

Modified residue

1049

Phosphoserine

Modified residue

2003

Phosphoserine

Modified residue

2022

Phosphoserine

Glycosylation

205

N-linked (GlcNAc...) asparagine

Glycosylation

1518

N-linked (GlcNAc...) asparagine

Glycosylation

1523

N-linked (GlcNAc...) asparagine

Glycosylation

1641

N-linked (GlcNAc...) asparagine

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Structure

Point mutationins R387E in alpha1E channels significantly influence both the kinetics and the voltage dependence of inactivation. [97]

Altogether our findings identify S6 hydrophobic residues in Domains I to IV that play a unique role in controlling the relative stability of the open and closes states in CaV2.3. [99]

Cav2.3 predicted AlphaFold size

Species	Area (Å²)	Reference
Human	10364.93	source
Mouse	11351.34	source
Rat	9793.66	source

Methodology for AlphaFold size prediction and disclaimer are available here

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Kinetics

R-type currents - mediated by Cav2.3 channels - participate in neurosecretion and in the formation of afterdepolarizations, plateau potentials, and bursting activity in hippocampal CA1 pyramidal neurons [514], [515], [516], [517].

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Biophysics

Model Ca_R (ID=7)

Animal	rat
CellType	Cerebellar
Age	21 Days
Temperature	36.0°C
Reversal	135.0 mV
Ion	Ca +
Ligand ion
Reference	[261] T Miyasho et. al; Brain Res. 2001 Feb 9
mpower	1.0
m Alpha	2.6/(1+exp((v+7)/-8))
m Beta	0.18/(1+exp((v+26)/4))
hpower	1.0
h Alpha	0.0025/(1+exp((v+32)/8))
h Beta	0.19/(1+exp((v+42)/-10))

MOD - xml - channelML

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CNS Sub-cellular Distribution

Cav2.3 channels are located in dendritic spines. [518]

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Function

Cav2.3 is involved in cerebellar function, morphine tolerance, and synaptic plasticity [519], [520], [521], [522], [523]. It is noteworthy that CaV2.3 is also implicated in nociception, as evidenced by the fact that CaV2.3 knockout mice exhibit functional deficits in pain per- ception [524] and intrathecal injection of SNX-482 produces analgesia [525].

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Interaction

G-alpha-q/11-coupled Muscarinic Acetylcholine

Cav2.3 is both inhibited and stimulated through G-alpha-q/11-coupled muscarinic acetylcholine receptors [526], [89].

Interaction with alpha1C channel

A chimeric channel containing the I-II linker from alpha1E (Cav2.3) accelerated the inactivation kinetics of alpha1C [527].

Mibefradil

Mibefradil (RO 40-5967), which has been used clinically as an anti-hypertensive and antianginal agent is modulating Ca2.3's inactivation kinetics. [100]

References

Meza U et al. Neurokinin 1 receptors trigger overlapping stimulation and inhibition of CaV2.3 (R-type) calcium channels.
Mol. Pharmacol., 2007 Jan , 71 (284-93).

Berrou L et al. Molecular determinants of inactivation within the I-II linker of alpha1E (CaV2.3) calcium channels.
Biophys. J., 2001 Jan , 80 (215-28).

Pérez-Alvarez A et al. Pharmacological and biophysical properties of Ca2+ channels and subtype distributions in human adrenal chromaffin cells.
Pflugers Arch., 2008 Sep , 456 (1149-62).

Raybaud A et al. The role of distal S6 hydrophobic residues in the voltage-dependent gating of CaV2.3 channels.
J. Biol. Chem., 2007 Sep 21 , 282 (27944-52).

100

Bernatchez G et al. State-dependent inhibition of inactivation-deficient Ca(V)1.2 and Ca(V)2.3 channels by mibefradil.
J. Membr. Biol., 2001 Nov 15 , 184 (143-59).

101

Cohen R et al. The C2A domain of synaptotagmin alters the kinetics of voltage-gated Ca2+ channels Ca(v)1.2 (Lc-type) and Ca(v)2.3 (R-type).
J. Biol. Chem., 2003 Mar 14 , 278 (9258-66).

102

Berrou L et al. A specific tryptophan in the I-II linker is a key determinant of beta-subunit binding and modulation in Ca(V)2.3 calcium channels.
Biophys. J., 2002 Sep , 83 (1429-42).

261

Miyasho T et al. Low-threshold potassium channels and a low-threshold calcium channel regulate Ca2+ spike firing in the dendrites of cerebellar Purkinje neurons: a modeling study.
Brain Res., 2001 Feb 9 , 891 (106-15).

340

Randall AD et al. Contrasting biophysical and pharmacological properties of T-type and R-type calcium channels.
Neuropharmacology, 1997 Jul , 36 (879-93).

512

Zhang JF et al. Distinctive pharmacology and kinetics of cloned neuronal Ca2+ channels and their possible counterparts in mammalian CNS neurons.
Neuropharmacology, 1993 Nov , 32 (1075-88).

513

Newcomb R et al. Selective peptide antagonist of the class E calcium channel from the venom of the tarantula Hysterocrates gigas.
Biochemistry, 1998 Nov 3 , 37 (15353-62).

514

Wu L et al. Dual regulation of voltage-gated calcium channels by PtdIns(4,5)P2.
Nature, 2002 Oct 31 , 419 (947-52).

515

Kuzmiski JB et al. Topiramate inhibits the initiation of plateau potentials in CA1 neurons by depressing R-type calcium channels.
Epilepsia, 2005 Apr , 46 (481-9).

516

Metz AE et al. R-type calcium channels contribute to afterdepolarization and bursting in hippocampal CA1 pyramidal neurons.
J. Neurosci., 2005 Jun 15 , 25 (5763-73).

517

Tai C et al. Muscarinic enhancement of R-type calcium currents in hippocampal CA1 pyramidal neurons.
J. Neurosci., 2006 Jun 7 , 26 (6249-58).

518

Sabatini BL et al. Analysis of calcium channels in single spines using optical fluctuation analysis.
Nature, 2000 Nov 30 , 408 (589-93).

519

Kubota M et al. Intact LTP and fear memory but impaired spatial memory in mice lacking Ca(v)2.3 (alpha(IE)) channel.
Biochem. Biophys. Res. Commun., 2001 Mar 23 , 282 (242-8).

520

Breustedt J et al. Alpha1E-containing Ca2+ channels are involved in synaptic plasticity.
Proc. Natl. Acad. Sci. U.S.A., 2003 Oct 14 , 100 (12450-5).

521

Dietrich D et al. Functional specialization of presynaptic Cav2.3 Ca2+ channels.
Neuron, 2003 Jul 31 , 39 (483-96).

522

Yokoyama K et al. Blocking the R-type (Cav2.3) Ca2+ channel enhanced morphine analgesia and reduced morphine tolerance.
Eur. J. Neurosci., 2004 Dec , 20 (3516-9).

523

Osanai M et al. Altered cerebellar function in mice lacking CaV2.3 Ca2+ channel.
Biochem. Biophys. Res. Commun., 2006 Jun 9 , 344 (920-5).

524

Saegusa H et al. Altered pain responses in mice lacking alpha 1E subunit of the voltage-dependent Ca2+ channel.
Proc. Natl. Acad. Sci. U.S.A., 2000 May 23 , 97 (6132-7).

525

Murakami M et al. Antinociceptive effect of different types of calcium channel inhibitors and the distribution of various calcium channel alpha 1 subunits in the dorsal horn of spinal cord in mice.
Brain Res., 2004 Oct 22 , 1024 (122-9).

526

Meza U et al. Biphasic, opposing modulation of cloned neuronal alpha1E Ca channels by distinct signaling pathways coupled to M2 muscarinic acetylcholine receptors.
J. Neurosci., 1999 Aug 15 , 19 (6806-17).

527

Stotz SC et al. Fast inactivation of voltage-dependent calcium channels. A hinged-lid mechanism?
J. Biol. Chem., 2000 Aug 11 , 275 (24575-82).

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Credits

Contributors: Rajnish Ranjan, Michael Schartner

To cite this page: [Contributors] Channelpedia https://channelpedia.epfl.ch/wikipages/82/ , accessed on 2024 Apr 26

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