Cav2.1

Description: calcium channel, voltage-dependent, P/Q type, alpha 1A subunit
Gene: Cacna1a
Alias: ca2.1, EA2, FHM, MHP, rkr, APCA, HPCA, MHP1, SCA6, Caca1a, Cav2.1, Ccha1a, Cacnl1a4, Cacna1a

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Introduction

The P/Q-type channels, also known as α1A or Cav2.1, are high voltage activated (HVA) calcium channels widespread throughout cortex. They function in both vesicle release and postsynaptic calcium entry. The α1 subunit is a principal subunit, localized in the cell membrane and forming a conductive pore. β, α2, δ, and γ are auxiliary subunits.

The β subunits are believed to enhance the trafficking of the channels to the plasma membrane by binding via their guanylate kinase (GK)-like domain to the a interaction domain (AID) on the I–II linker of all theHVAa subunits [251].

See also the Channelpedia entry for Cav2.2 which is similar to Cav2.1 in many respects.

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Gene

Genbank 25398, Cacna1a calcium channel, voltage-dependent, P/Q type, alpha 1A subunit [ Rattus norvegicus ], also known as BccA1; rbA-1; Cav2.1; Cacna1a

The alpha 2.1 (alpha 1A) subunits of P-type and Q-type Ca 2+ channels are encoded by a single gene, Cacna1a. [85]

Species	NCBI gene ID	Chromosome	Position
Human	773	19	300037
Mouse	12286	8	301623
Rat	25398	19	299230

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Transcript

Species	NCBI accession	Length (nt)
Human	NM_000068.4	8660
Mouse	NM_007578.3	7929
Rat	NM_012918.4	8915

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Protein Isoforms

Species	Uniprot ID	Length (aa)
Human	O00555	2506
Mouse	P97445	2368
Rat	P54282	2212

Isoforms

Transcript

Length (nt)

Protein

Length (aa)

Variant

Isoform

Known

NM_001127222.2

8647

NP_001120694.1

2506

transcript variant 4

isoform 4

NM_001127221.2

8645

NP_001120693.1

2261

transcript variant 3

isoform 3

NM_001174080.2

8651

NP_001167551.1

2263

transcript variant 5

isoform 5

NM_000068.4

8660

NP_000059.3

2266

transcript variant 1

isoform 1

NM_023035.3

8665

NP_075461.2

2512

transcript variant 2

isoform 2

Known

NM_007578.3

7929

NP_031604.3

2368

transcript variant 1

isoform 1

NM_001252060.1

7778

NP_001238989.1

2327

transcript variant 3

isoform 3

NM_001252061.1

7921

NP_001238990.1

2285

transcript variant 4

isoform 4

NM_001252059.1

7788

NP_001238988.1

2321

transcript variant 2

isoform 2

Predicted

XR_003947223.2

6847

transcript variant X26

XR_003947224.2

6841

transcript variant X27

XR_003947227.2

6757

transcript variant X32

XR_004934753.1

6828

transcript variant X28

XR_003947226.2

6102

transcript variant X31

XR_003947222.2

9346

transcript variant X24

XR_003947221.2

8424

transcript variant X23

XM_006530609.4

5674

XP_006530672.1

1704

transcript variant X29

isoform X24

XM_036153733.1

5664

XP_036009626.1

1704

transcript variant X30

isoform X24

XM_006530605.5

6225

XP_006530668.1

1890

transcript variant X25

isoform X23

XM_006530587.5

8395

XP_006530650.1

2464

transcript variant X1

isoform X1

XM_011248285.4

8256

XP_011246587.1

2427

transcript variant X19

isoform X19

XM_006530603.5

8390

XP_006530666.1

2308

transcript variant X20

isoform X20

XM_006530601.5

8359

XP_006530664.1

2452

transcript variant X15

isoform X15

XM_030243261.2

8354

XP_030099121.1

2296

transcript variant X21

isoform X21

XM_006530588.5

8395

XP_006530651.1

2464

transcript variant X2

isoform X2

XM_036153732.1

8359

XP_036009625.1

2452

transcript variant X16

isoform X16

XM_030243262.2

8354

XP_030099122.1

2296

transcript variant X22

isoform X22

XM_006530592.5

8389

XP_006530655.1

2462

transcript variant X6

isoform X6

XM_006530593.5

8389

XP_006530656.1

2462

transcript variant X7

isoform X7

XM_006530602.4

8305

XP_006530665.1

2434

transcript variant X18

isoform X18

XM_006530595.5

8383

XP_006530658.1

2460

transcript variant X9

isoform X9

XM_006530596.5

8383

XP_006530659.1

2460

transcript variant X10

isoform X10

XM_006530598.5

8377

XP_006530661.1

2458

transcript variant X12

isoform X12

XM_006530589.5

8392

XP_006530652.1

2463

transcript variant X3

isoform X3

XM_006530591.5

8389

XP_006530654.1

2462

transcript variant X5

isoform X5

XM_006530600.5

8371

XP_006530663.1

2456

transcript variant X14

isoform X14

XM_006530590.5

8392

XP_006530653.1

2463

transcript variant X4

isoform X4

XM_006530594.5

8386

XP_006530657.1

2461

transcript variant X8

isoform X8

XM_006530599.5

8366

XP_006530662.1

2457

transcript variant X13

isoform X13

XM_030243260.2

8319

XP_030099120.1

2446

transcript variant X17

isoform X17

XM_006530597.5

7834

XP_006530660.1

2458

transcript variant X11

isoform X11

Known

NM_012918.4

8915

NP_037050.3

2368

Predicted

XR_005496615.1

6029

transcript variant X17

XR_005496617.1

5885

transcript variant X19

XR_005496616.1

5749

transcript variant X18

XM_039097490.1

8102

XP_038953418.1

2388

transcript variant X13

isoform X13

XM_039097483.1

8320

XP_038953411.1

2461

transcript variant X6

isoform X6

XM_039097481.1

8323

XP_038953409.1

2462

transcript variant X4

isoform X4

XM_039097480.1

8323

XP_038953408.1

2462

transcript variant X3

isoform X3

XM_039097478.1

8326

XP_038953406.1

2463

transcript variant X1

isoform X1

XM_039097479.1

8326

XP_038953407.1

2463

transcript variant X2

isoform X2

XM_039097487.1

8304

XP_038953415.1

2456

transcript variant X10

isoform X10

XM_039097484.1

8313

XP_038953412.1

2459

transcript variant X7

isoform X7

XM_039097482.1

8319

XP_038953410.1

2461

transcript variant X5

isoform X5

XM_039097489.1

8283

XP_038953417.1

2449

transcript variant X12

isoform X12

XM_039097486.1

8306

XP_038953414.1

2457

transcript variant X9

isoform X9

XM_039097485.1

8306

XP_038953413.1

2457

transcript variant X8

isoform X8

XM_039097488.1

7768

XP_038953416.1

2451

transcript variant X11

isoform X11

XM_039097491.1

7432

XP_038953419.1

2307

transcript variant X14

isoform X14

XM_039097492.1

6150

XP_038953420.1

1889

transcript variant X15

isoform X15

XM_039097493.1

7488

XP_038953421.1

1727

transcript variant X16

isoform X16

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Post-Translational Modifications

PTM

Position

Type

Modified residue

409

Phosphothreonine

Modified residue

447

Phosphoserine

Modified residue

450

Phosphoserine

Modified residue

749

Phosphoserine

Modified residue

752

Phosphoserine

Modified residue

789

Phosphoserine

Modified residue

1084

Phosphoserine

Modified residue

1093

Phosphoserine

Modified residue

1983

Phosphothreonine

Modified residue

2046

Phosphoserine

Modified residue

2064

Phosphoserine

Modified residue

2076

Phosphoserine

Modified residue

2078

Phosphoserine

Modified residue

2119

Phosphoserine

Modified residue

2139

Phosphoserine

Glycosylation

283

N-linked (GlcNAc...) asparagine

Modified residue

411

Phosphothreonine

Modified residue

450

Phosphoserine

Modified residue

453

Phosphoserine

Modified residue

752

Phosphoserine

Modified residue

755

Phosphoserine

Modified residue

792

Phosphoserine

Modified residue

1038

Phosphoserine

Modified residue

1042

Phosphoserine

Modified residue

1051

Phosphoserine

Modified residue

1935

Phosphothreonine

Modified residue

1998

Phosphoserine

Modified residue

2016

Phosphoserine

Modified residue

2028

Phosphoserine

Modified residue

2030

Phosphoserine

Modified residue

2071

Phosphoserine

Modified residue

2091

Phosphoserine

Glycosylation

285

N-linked (GlcNAc...) asparagine

Glycosylation

1607

N-linked (GlcNAc...) asparagine

Modified residue

411

Phosphothreonine

Modified residue

450

Phosphoserine

Modified residue

453

Phosphoserine

Modified residue

752

Phosphoserine

Modified residue

755

Phosphoserine

Modified residue

792

Phosphoserine

Modified residue

1038

Phosphoserine

Modified residue

1042

Phosphoserine

Modified residue

1051

Phosphoserine

Modified residue

1935

Phosphothreonine

Modified residue

1998

Phosphoserine

Modified residue

2016

Phosphoserine

Modified residue

2028

Phosphoserine

Modified residue

2030

Phosphoserine

Modified residue

2071

Phosphoserine

Modified residue

2091

Phosphoserine

Glycosylation

285

N-linked (GlcNAc...) asparagine

Glycosylation

1607

N-linked (GlcNAc...) asparagine

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Structure

When compared with other Ca channels, the Cav2.1 (rbA) channel is notably different in both the carboxyl terminus and in a large (474-amino acid) hydrophilic segment between domains II and HI. [475]

Cav2.1 predicted AlphaFold size

Species	Area (Å²)	Reference
Human	9393.87	source
Mouse	15401.61	source
Rat	9148.78	source

Methodology for AlphaFold size prediction and disclaimer are available here

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Biophysics

The most detailed model can be found in [250]. It is from hippocampal mossy fiber boutons.

A detailed compartmental model of a Purkinje neuron, taking into account two types of low-threshold Ca 21 channel (T-type and class-E, or R-type) and two types of low-threshold K 1 channel (A-type and D-type), in addition to another eight voltage-gated channel types, using the program NEURON. [261]

Model Ca_P/Q (ID=5)

Junction potential corrected model

Animal	rat
CellType	Cerebellar Purkinje
Age	21 Days
Temperature	21.0°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	8.5/(1+exp((v-8)/(-12.5)))
m Beta	35/(1+exp((v+74)/(14.5)))

MOD - xml - channelML

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Expression and Distribution

Predominantly expressed in the cerebellar Purkinje cells and granule cells [474].

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CNS Sub-cellular Distribution

CaV 2.1 channels are widely distributed in the presynaptic terminals and somatodendritic membranes throughout the brain [474].

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Function

P/Q-type calcium channels (Cav2.1) play an important role in mediating neurotransmitter release in the nervous system, postsynaptic integration, neuroplasticity, neural excitability, and gene transcription [471], [472], [473].

Malfunction of Cav2.1 brings about the disease spinocerebellar ataxia type 6. [83].

Mutations in the gene encoding the pore-forming α1A subunit of P/Q Ca2+ channels (CACNA1A) are linked to familial hemiplegic migraine. [87]

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Interaction

G proteins, calmodulin

Omega-agatoxin-IVA

High sensitivity to the funnel web spider venom Omega-agatoxin-IVA. Mintz [555]

Roscovitine

Roscovitine, a potent inhibitor of cyclin-dependent kinases 1, 2, and 5, slows the deactivation of P/Q (Cav2.2) and N-type (CaV2.1) calcium channels. [93]

References

Miki T et al. Two novel alleles of tottering with distinct Ca(v)2.1 calcium channel neuropathologies.
Neuroscience, 2008 Jul 31 , 155 (31-44).

Chen H et al. Altered frequency-dependent inactivation and steady-state inactivation of polyglutamine-expanded alpha1A in SCA6.
Am. J. Physiol., Cell Physiol., 2007 Mar , 292 (C1078-86).

Tanaka K et al. Increased Ca2+ channel currents in cerebellar Purkinje cells of the ataxic groggy rat.
Neurosci. Lett., 2007 Oct 16 , 426 (75-80).

Tsunemi T et al. Novel Cav2.1 splice variants isolated from Purkinje cells do not generate P-type Ca2+ current.
J. Biol. Chem., 2002 Mar 1 , 277 (7214-21).

Hans M et al. Structural elements in domain IV that influence biophysical and pharmacological properties of human alpha1A-containing high-voltage-activated calcium channels.
Biophys. J., 1999 Mar , 76 (1384-400).

Serra SA et al. The hemiplegic migraine-associated Y1245C mutation in CACNA1A results in a gain of channel function due to its effect on the voltage sensor and G-protein-mediated inhibition.
Pflugers Arch., 2009 Jul , 458 (489-502).

Buraei Z et al. Slowed N-type calcium channel (CaV2.2) deactivation by the cyclin-dependent kinase inhibitor roscovitine.
Biophys. J., 2005 Sep , 89 (1681-91).

250

Li L et al. Differential gating and recruitment of P/Q-, N-, and R-type Ca2+ channels in hippocampal mossy fiber boutons.
J. Neurosci., 2007 Dec 5 , 27 (13420-9).

251

Dolphin AC Calcium channel diversity: multiple roles of calcium channel subunits.
Curr. Opin. Neurobiol., 2009 Jun , 19 (237-44).

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).

471

Llinás R et al. Distribution and functional significance of the P-type, voltage-dependent Ca2+ channels in the mammalian central nervous system.
Trends Neurosci., 1992 Sep , 15 (351-5).

472

Mintz IM et al. P-type calcium channels in rat central and peripheral neurons.
Neuron, 1992 Jul , 9 (85-95).

473

Sutton KG et al. P/Q-type calcium channels mediate the activity-dependent feedback of syntaxin-1A.
Nature, 1999 Oct 21 , 401 (800-4).

474

Ludwig A et al. Regional expression and cellular localization of the alpha1 and beta subunit of high voltage-activated calcium channels in rat brain.
J. Neurosci., 1997 Feb 15 , 17 (1339-49).

475

Starr TV et al. Primary structure of a calcium channel that is highly expressed in the rat cerebellum.
Proc. Natl. Acad. Sci. U.S.A., 1991 Jul 1 , 88 (5621-5).

476

Currie KP G protein modulation of CaV2 voltage-gated calcium channels.
Channels (Austin), 2010 Nov-Dec , 4 (497-509).

555

Mintz IM et al. Block of calcium channels in rat neurons by synthetic omega-Aga-IVA.
Neuropharmacology, 1993 Nov , 32 (1161-9).

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Credits

Contributors: Rajnish Ranjan, Michael Schartner

To cite this page: [Contributors] Channelpedia https://channelpedia.epfl.ch/wikipages/78/ , accessed on 2024 Apr 24

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