Channelpedia

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

Edit - History

Introduction

Cav2.1, encoded by the gene cacna1a, is a calcium channel, voltage-dependent, P/Q type, alpha 1A subunit . It is primarily expressed in the central nervous system and is responsible for controlling neurotransmitter release and neuronal excitability.


Edit - History

Gene

In humans, Cacna1a, the gene which encodes Cav2.1, is composed of 49 exons located on chromosome 19 at position 13. (19p13.13). [2427]

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

Edit - History

Transcript

Like most Cav channels, Cacna1a is subject to alternative splicing. Seven exonic loci of the CaV2.1 gene have been shown to undergo alternative splicing

Some important exons, often involved in alternative splicing are:

  • Exon 47, which code for part of the C-terminal [2428]
  • Exon 37a/b, whose expression is mutually exclusive, which code for part of the F helix of the EF-hand domain [Ref]
Species NCBI accession Length (nt)
Human NM_000068.4 8660
Mouse NM_007578.3 7929
Rat NM_012918.4 8915

Edit - History

Protein Isoforms

The human Cav2.1 protein is composed of 2506 amino acid (aa) and has a molecular weight of 282 Kda. The CACNA1A gene undergoes extensive alternative splicing, resulting in P/Q channels with different properties. These splice variants are differentially expressed throughout the CNS, and serve to adjust the biophysical parameters of the individual channel to correspond with its role in the various cell types. [2427]

For example, hippocampal synapses expressing Cav2.1 either with exon 47 (CaV2.1+47) or without (CaV2.1Δ47) differ in release probability and short-term plasticity [2428]. CaV2.1 channels that include exon EFb show calcium-dependent facilitation (CDF) only without exon 47 inclsuion, while CaV2.1 + EFa channels show robust CDF regardless of exon 47.

Expression of the variants and isoforms also differ between species. During development, rodent brains switch from high EFb to high EFa expression, but in humans, EFb and EFa expression is biphasic and varies with age and gender. EFa and EFb also show subcellular compartmentalization in neurons. [Ref]

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

Isoforms

Transcript
Length (nt)
Protein
Length (aa)
Variant
Isoform

Edit - History

Post-Translational Modifications

To date there is no research on PTMS that affect Cav2.1

PTM
Position
Type

Edit - History

Structure

Like most Cav channels, Cav2.1 is made up of a single protein composed of 4 homologous domains (DI-DIV). Each domain is made up of 6 transmembrane subunits (S1-S6) connected by extracellular loops. S1-4 form the voltage sensing domain (VSD) whereas the S5-S6 act as the selectivity filter and form the pore module (PM). The S4 subunit of each domain contains a series of positively charged residues. The N-terminus and C-terminus of the α1 subunit have important roles in trafficking and anchoring of the subunit to the cell membrane. The C-terminus contains an Ile–Gln calmodulin-binding motif that helps to regulate calcium-dependent facilitation and inactivation of the channel.13 The intracellular loop between domains II and III of the α1 subunit contains a domain that can interact with G-protein-coupled receptors, as well as key motifs that interact with SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins, which are important for vesicular docking before exocytosis [2427]

The structure of Cav2.1 was resolved via electron-microscopy, giving us a detailed insight into the specific structural features the protein [2429] The overall structure of Cav2.1 closely resembles those of Cav2.2 and Cav2.3. The differences are mostly present in the extracellular loops in repeats I and IV, consistent with the sequence variations of these regions. This divergence in ECLs underlies the distinctive sensitivities of Cav2 channels to various peptide toxins [2429]

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


Edit - History

Kinetics

Human CaV2.1 channels exhibit two distinct gating modes: slow and fast. In the slow mode, the channels have longer mean closed times and longer latency to first opening. Activation in the slow mode requires larger depolarizations, and inactivation kinetics are slower. Steady-state inactivation occurs at less negative voltages in the slow mode. Channels lacking a β subunit primarily operate in a low-po mode, which differs from both the slow and fast modes. In the low-po mode, the channels have shorter mean open times, longer mean closed times, longer first latency, a higher fraction of nulls, and activate at more positive voltages with a shallower voltage dependence. [2430]


Edit - History

Biophysics

Single channel unitary conductance

The single channel unitary conductance of Cav2.1 was measured between 9–19 pS. [2431] Single channel unitary conductance can change depending on experimental conditions and co-expressed subunits. The single channel unitary conductance of Cav2.1 is 19.5 pS for channels containing the β1b subunit, 20 pS for channels containing the β2e subunit, 19 pS for channels containing the β3a subunit, and 20 pS for channels containing the β4a subunit. [2430]

Model


Model Ca_P/Q (ID=5)      

Junction potential corrected model

Animalrat
CellType Cerebellar Purkinje
Age 21 Days
Temperature21.0°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


Edit - History

Expression and Distribution

The designation P/Q reflects the cell types from which its constituent currents were first isolated: the letter P is derived from Purkinje cells, and the letter Q refers to granule cells of the cerebellum where the channel is highly expressed. [2427]

Cav2.1 expression is almost exclusively restricted to neuronal and neuroendocrine (such as pituitary and pancreatic β) cells . The P/Q channel is widely expressed throughout the CNS but is particularly abundant in Purkinje and granule cells of the cerebellum [2427] but has also been identified in the cerebral cortex, thalamus, hypothalamus, hippocampus [2415]


Edit - History

CNS Sub-cellular Distribution

Cav2.1 is predominantly localized at the presynaptic terminal, where they play a prominent role in controlling neurotransmitter release. They are also present at the somatodendritic membranes where they control certain postsynaptic events, such as neuronal excitability. [2432]

Within these locations, Cav2.1 exists in clusters of on average 18 channels [2433]


Edit - History

Function

pivotal role in controlling neurotransmitter release from the pre-synaptic button and regulation of the firing behaviour through the integration of dendritic signals and generation of dendritic spikes. [2434] [2435] [2432]

The Cav2.1 channels also have indispensable roles in the postnatal development of the cerebellar circuitry. Cav2.1 fuels heterosynaptic competition between climbing and parallel fibers and also homosynaptic competition among multiple climbing fibers in developing cerebellum [2435]

Cav2.1 is also plays a calcium regulation role which contributes to the short term synaptic plasticity in certain neurons (hippocampal). Aberrant manipulation to the protein, particularly the CaM binding sites, lead to a reduction synaptic transmission facilitation and in turn a reduction in synaptic plasticity [2436] [2437]

Channelopathies

Given the importance of Cav2.1’s role in the brain, mutations to coding gene or protein are responsible for a number of pathologies

Familial hemiplegic migraine type 1 (FHM-1) is a Mendelian subtype of migraine with aura that is caused by missense mutations in the CACNA1A gene. FHM-1 mutation lead to gain-of-function of excitatory neurotransmission , including increased Cav2.1 current density in cerebellar neurons, enhanced neurotransmission at the neuromuscular junction, and, a reduced threshold and increased velocity of cortical spreading depression [2432]

Mutation to Cav2.1 are also responsible for different types of Ataxia: Spinocerebellar Ataxia type 6 (SCA6) and Episodic Ataxia type 2 (EA2) [2438].

  • SCA6 results from an expansion of ‘CAG’ polyglutamine repeats in COOH tail of CACNA1A protein. This results in a toxic gain-of-function affecting channel regulation leading to the selective degeneration of cerebellar Purkinje cells (8988170)
  • SCA2 results from loss-of-function mutations leading to decreased channel function and thereby a decrease in intracellular Ca 2+

Other mutation to CACNA1A gene are responsible for certain types of epileptic encephalopathies (EEs) [2439]

On top of causing own set of diseases, changes to Cav1.2 also accompany other diseases. Most cases with CACNA1A variants present with ataxia, epilepsy, attention deficit hyperactive disorder, autism spectrum disorder, dysmorphic features and eye abnormalities such as nystagmus, paroxysmal tonic upgaze, dysmetric saccades, blindness, myoclonus, ocular apraxia, exophthalmos and bilateral esotropia. Schizophrenia, anxiety, depression, hemiplegic migraine, coma, conductive deafness, vertigo attacks, dysarthria, tremors, athetosis, optic nerve glioma, abnormal behaviors such as aggression, sleeping problems can also be noticed. [2415] Cav2.1 is also regularly under-expressed in certain cancers, such as the brain or breast [2440]


Edit - History

Interaction

Auxiliary subunit

Cav2.1 channels typically exist as multi-subunit complexes comprised of the main pore-forming α1 subunit, as previously described, and auxiliary subunits α2δ-2, β2 subunits [2373] The β and α2δ auxiliary subunits coassemble with the α1 subunit in a 1:1:1 stoichiometric ratio and influence both trafficking and kinetic properties of the pore-forming subunits [2441] [2427] Four different α2δ subunits have been described (α2δ-1 to α2δ-4), which may interact with Cav2.1 at different degrees of association [2441] Four Cav-β subunits (β1b, β2e, β3a, or β4a) have been identified differentially expressed in neurons and are able to interact with Cav2.1. The type of β subunit modulates the occurrence of these modes and their inactivation properties. As all four subunits can act on Cav2.1 simultaneously, which combination of β subunits interactions occur will also influence the final properties the channel. Without β subunits, CaV2.1 channels show shorter open times, longer closed times, longer first latency, more nulls, and require higher voltage for activation. [2430]

Calcium & CaM

Cav2.1 allows the passage of Ca2+ ions in and out of the cell. However, it is itself sensitive to the fluctuation concentrations of the ion and can undergo Ca2+ dependent inactivation thanks to its interaction with certain proteins, namely CAM. [2442] Binding of CaM occurs at the C-terminus, which contains an Ile–Gln calmodulin-binding. [2427]

It is though that Ca(2+)-free CaM, apoCaM may "pre-associate" with these Cav2.1 to enhance detection of local Ca(2+). [2443]

Other Proteins

The intracellular loops of Cav2.1, between domains II and III, t contains a domain that can interact with G-protein-coupled receptors, as well as key motifs that interact with SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins. G protein coupled receptors are established to orchestrate precise regulation of neurotransmitters and hormone release through inhibition of CaV2 channels. SNARE proteins are important for vesicular docking before exocytosis [2427] [476]

RIM-binding proteins (RIM-BPs) are multidomain active zone proteins that bind to RIMs and to Ca(2+) channels. RIM-BPs are not essential for neurotransmitter release, but are required for high-fidelity coupling of action potential-induced Ca(2+) influx to Ca(2+)-stimulated synaptic vesicle exocytosis. Deletion of RIM-BPs decelerated action-potential-triggered neurotransmitter release and rendered it unreliable, thereby impairing the fidelity of synaptic transmission. [2444]

Bassoon is a presynaptic scaffolding protein Bassoon localized specifically to active zones, similarly ot Cav2.1, at the active zone (CAZ) where neurotransmitter is released- This is done via molecular interaction with the RIM-binding proteins (RBPs). A genetic deletion of Bassoon or interference with Bassoon-RBP interaction reduces synaptic numbers of CaV2.1 and weakens P/Q-type Ca(2+) current-driven synaptic transmission [2434]

Laminin beta2 is a component of the synaptic cleft at the neuromuscular junction. Laminin beta2 binds directly to calcium channels, including Cav2.1, that are required for neurotransmitter release from motor nerve terminals. This interaction leads to clustering of channels, which in turn recruits other presynaptic components. Perturbation of this interaction in vivo results in disassembly of neurotransmitter release sites [2445]

Large-conductance calcium- and voltage-activated potassium channels (BKCa) are activated by both membrane depolarization and elevation of cytosolic calcium ions (Ca2+). Under physiological conditions, BKCa channel activation requires Ca2+ concentrations that typically occur in close proximity to Ca2+ sources. Based on this knowledge, BKCa channels were shown to assemble into macromolecular complexes with the voltage-gated calcium channels including, Cav1.2 (L-type), Cav2.1 (P/Q-type), and Cav2.2 (N-type). [2446]

Nrxns are polymorphic synaptic cell adhesion molecules, for which multiple presynaptic and postsynaptic ligands exist. Whole-cell patch-clamp recordings show that Nrxn1α in combination with α2δ-1, but not with α2δ-3, facilitates Ca2+ currents of recombinant CaV2.1 without altering channel kinetics. Though not acting directly of Cav2.1 presynaptic Nrxn1α does act as a positive regulator of Ca2+ influx through CaV2.1 channels containing α2δ-1 subunits [2441]

Cav2.1 has a high sensitivity to the funnel web spider venom Omega-agatoxin-IVA. [555]

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]


- History

References

82

83

84

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).

85

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).

251

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

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).

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).

Hofmann F et al. L-type CaV1.2 calcium channels: from in vitro findings to in vivo function.
Physiol. Rev., 2014 Jan , 94 (303-26).

Kessi M et al. Calcium channelopathies and intellectual disability: a systematic review.
Orphanet J Rare Dis, 2021May13, 16 (219).

Sutherland HG et al. Advances in genetics of migraine.
J Headache Pain, 2019Jun21, 20 (72).

Phan NN et al. Voltage-gated calcium channels: Novel targets for cancer therapy.
Oncol Lett, 2017Aug, 14 (2059-2074).

Berkefeld H et al. BKCa-Cav channel complexes mediate rapid and localized Ca2+-activated K+ signaling.
Science, 2006 Oct 27 , 314 (615-20).


Edit - History

Credits

Contributors: Katherine Johnston, Rajnish Ranjan, Michael Schartner

To cite this page: [Contributors] Channelpedia https://channelpedia.epfl.ch/wikipages/78/ , accessed on 2024 Dec 02