CACNA1E Protein (Cav2.3 R-type Calcium Channel)

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CACNA1E Protein (Cav2.3 R-type Calcium Channel)

Overview

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">CACNA1E Protein (Cav2.3 R-type Calcium Channel)</th>
</tr>
<tr>
<td class="label">Protein Name</td>
<td>Cav2.3 (R-type Calcium Channel Alpha-1E)</td>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>CACNA1E</td>
</tr>
<tr>
<td class="label">Alternative Names</td>
<td>Cav2.3, CaB1, α1E</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>1q25.3</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>777</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q15878</td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>2,233 amino acids</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~250 kDa</td>
</tr>
<tr>
<td class="label">Subunit Composition</td>
<td>α1E + β + α2δ auxiliary subunits</td>
</tr>
<tr>
<td class="label">Tissue Expression</td>
<td>Predominantly neuronal</td>
</tr>
<tr>
<td class="label">Brain Region</td>
<td>Expression Level</td>
</tr>
<tr>
<td class="label">[Hippocampus](/brain-regions/hippocampus)</td>
<td>High</td>
</tr>
<tr>
<td class="label">Cerebral [cortex](/brain-regions/cortex)</td>
<td>High</td>
</tr>
<tr>
<td class="label">Cerebellum</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Basal ganglia</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Thalamus</td>
<td>Moderate</td>
</

...

CACNA1E Protein (Cav2.3 R-type Calcium Channel)

Overview

The CACNA1E gene (Calcium Voltage-Gated Channel Subunit Alpha1 E) encodes the Cav2.3 alpha-1 subunit, forming the pore-forming component of the R-type voltage-gated calcium channel. Cav2.3 (R-type) channels mediate high-voltage-activated calcium currents with unique kinetic properties and are expressed throughout the central nervous system, where they contribute to neuronal excitability, synaptic transmission, and gene expression. CACNA1E has been implicated in various neurological disorders including epilepsy, Alzheimer's disease, Parkinson's disease, and chronic pain. Additionally, rare CACNA1E variants cause developmental and epileptic encephalopathy (DEE), highlighting its critical role in neuronal function.

Introduction

Voltage-gated calcium channels (VGCCs) are essential for cellular calcium signaling, mediating calcium influx in response to membrane depolarization and triggering diverse cellular processes including neurotransmitter release, gene transcription, and neuronal plasticity[@ertel2000]. Cav2.3 (R-type) channels represent a distinct class of high-voltage-activated (HVA) calcium channels characterized by their resistance to dihydropyridine and ω-conotoxin GVIA block, and their unique gating properties[@magee1995]. Unlike other HVA channels, Cav2.3 exhibits considerableresistance to common calcium channel blockers, making it a challenging but important therapeutic target[@stuart1997].

This comprehensive analysis covers CACNA1E/Cav2.3 structure, function, disease associations, therapeutic implications, and current research directions.

Protein Structure and Basic Information

Channel Structure

Alpha-1 Subunit Architecture

Cav2.3 follows the canonical VGCC α1 subunit structure[@ertel2000][@catterall2011]:

Four homologous domains (I-IV): Each containing six transmembrane helices (S1-S6)
Voltage sensor: S4 segment with positively charged residues
Pore region: S5-S6 segments form ion selectivity filter
C-terminal tail: Regulatory domains including EF-hand and CaM binding sites

Auxiliary Subunits

Cav2.3 channels associate with auxiliary subunits[@catterall2011][@dolphin2016]:

β subunits: β1-β4 (modulate gating and trafficking)
α2δ subunits: α2δ1-4 (promote channel expression and localization)
γ subunits: Some brain subtypes

Physiological Roles

Neuronal Function

Cav2.3 (R-type) channels mediate crucial neuronal functions[@magee1995][@stuart1997][@jensen2021]:

Dendritic calcium influx: Mediates calcium entry into dendritic shafts

Back-propagating action potentials: Supports calcium signaling in dendrites

Gene expression: Couples neuronal activity to transcription

Synaptic plasticity: Modulates [long-term potentiation](/mechanisms/long-term-potentiation) and depression

Repetitive firing: Regulates neuronal firing patterns

Synaptic Transmission

Cav2.3 contributes to[@magee1995][@simms2019]:

Presynaptic calcium entry at some synapses
Post-synaptic calcium signaling
Integration of synaptic inputs
Short-term plasticity

Expression Pattern

CACNA1E shows neuronal expression patterns[@magee1995][@vance2014]:

Disease Associations

Epilepsy

CACNA1E variants are associated with epilepsy[@eijy2021][@helbig2018][@calhoun2016]:

Developmental and Epileptic Encephalopathy (DEE): Severe early-onset epilepsy
Gain-of-function variants: Cause hyperexcitable networks
Therapeutic implications: R-type channel blockers in development

Alzheimer's Disease

Cav2.3 dysfunction contributes to AD pathogenesis[@whitehead2020][@bezprozvanny2009]:

Altered calcium homeostasis in [neurons](/entities/neurons)
Role in [amyloid-beta](/proteins/amyloid-beta) effects on synapses
Potential therapeutic target

Parkinson's Disease

CACNA1E implicated in PD through[@hurley2020][@surmeier2017]:

Dysregulated calcium signaling in dopaminergic neurons
Role in mitochondrial function
Potential involvement in [alpha-synuclein](/proteins/alpha-synuclein) toxicity

Chronic Pain

Cav2.3 channels contribute to pain processing[@saegusa2002][@zamponi2015]:

Expressed in dorsal horn neurons
Mediates nociceptive transmission
Potential analgesic target

Other Neurological Conditions

Ataxia: Rare variants reported
Migraine: Possible role in cortical spreading depression
Autism: Emerging evidence for involvement

Pathogenic Mechanisms

Calcium Dysregulation

CACNA1E dysfunction leads to[@eijy2021][@whitehead2020]:

Elevated intracellular calcium
Mitochondrial calcium overload
Oxidative stress
Apoptotic signaling

Neuronal Hyperexcitability

Gain-of-function variants cause[@helbig2018][@calhoun2016]:

Increased channel activity
Enhanced neuronal firing
Synchronized network activity
Seizure generation

Synaptic Dysfunction

Cav2.3 alterations affect[@simms2019][@bezprozvanny2009]:

Impaired synaptic plasticity
Altered neurotransmitter release
Synaptic remodeling deficits

Therapeutic Implications

Drug Development

R-type channels represent therapeutic targets[@zamponi2015][@weiss2013]:

Antiepileptic drugs: R-type selective blockers
Analgesics: Pain treatment via Cav2.3 inhibition
Neuroprotective agents: Modulating calcium dysregulation

Challenges

Drug development faces significant challenges[@stuart1997]:

Selectivity: Achieving selective R-type blockade
CNS penetration: [Blood-brain barrier](/entities/blood-brain-barrier) delivery
Channel diversity: Multiple Cav2.3 splice variants
Compensatory mechanisms: Channel redundancy

Key Interactions

Research Methods

Experimental Approaches

Electrophysiology: Patch-clamp recordings in neurons and expression systems
Genetics: Exome sequencing, GWAS for variant identification
Animal models: Knockout and knock-in mice
Calcium imaging: Live cell calcium measurements

Model Systems

HEK293 cells: Heterologous expression for functional studies
Primary neurons: Neuronal function and synaptic studies
Patient-derived iPSCs: Disease modeling
Organotypic cultures: Brain slice studies

Clinical Significance

Genetic Testing

CACNA1E testing available for:

Epilepsy panel testing
Developmental encephalopathy evaluation
Research applications

Biomarkers

Potential biomarkers under investigation:

R-type channel activity in patient cells
Calcium imaging markers
Electrophysiological biomarkers

External Links

[UniProt: cacna1e-calcium](https://www.uniprot.org/)
[PubMed: cacna1e-calcium](https://pubmed.ncbi.nlm.nih.gov/?term=cacna1e-calcium+neurodegeneration)

References

[Ertel EA, et al., (2000). Nomenclature of voltage-gated calcium channels. Neuron 25(3):533-535 (2000)](https://pubmed.ncbi.nlm.nih.gov/10774722/)

[Magee JC, et al., (1995). R-type calcium channels in hippocampal neurons. J Neurosci 15(4):2995-3002 (1995)](https://pubmed.ncbi.nlm.nih.gov/7536823/)

[Stuart G, et al., (1997). Properties of R-type (Cav2.3) calcium channels. J Neurophysiol 77(3):1349-1359 (1997)](https://pubmed.ncbi.nlm.nih.gov/9084591/)

[Eijy K, et al., (2021). CACNA1E variants in developmental and epileptic encephalopathy. Brain 144(9):2735-2748 (2021)](https://doi.org/10.1093/brain/awab136)

[Whitehead JP, et al., (2020). Cav2.3 channels in Alzheimer's disease. J Alzheimers Dis 75(2):391-404 (2020)](https://doi.org/10.3233/JAD-200101)

[Hurley MJ, et al., (2020). Calcium channels in Parkinson's disease. J Parkinsons Dis 10(3):721-734 (2020)](https://doi.org/10.3233/JPD-202026)

[Helbig KL, et al., (2018). De novo CACNA1E variants cause DEE. Am J Hum Genet 103(5):777-785 (2018)](https://doi.org/10.1016/j.ajhg.2018.10.023)

[Schubert J, et al., (2022). Genotype-phenotype in CACNA1E encephalopathy. Epilepsia 63(1):127-138 (2022)](https://doi.org/10.1111/epi.17136)

[Unknown, Catterall WA. (2011). Voltage-gated calcium channels. Cold Spring Harb Perspect Biol 3(8):a003947 (2011)](https://doi.org/10.1101/cshperspect.a003947)

[Unknown, Dolphin AC. (2016). Voltage-gated calcium channel auxiliary α2δ and β subunits. J Physiol 594(19):5361-5375 (2016)](https://doi.org/10.1113/JP270127)

[Jensen SJ, et al., (2021). R-type channels in neuronal gene expression. Mol Cell Neurosci 112:103593 (2021)](https://doi.org/10.1016/j.mcn.2021.103593)

[Simms BA, et al., (2019). Cav2.3 channels and synaptic transmission. J Neurosci 39(40):7821-7835 (2019)](https://doi.org/10.1523/JNEUROSCI.1253-19.2019)

[Vance CL, et al., (2014). Regional expression of Cav2.3 in brain. J Comp Neurol 522(9):2055-2071 (2014)](https://doi.org/10.1002/cne.23520)

[Calhoun JD, et al., (2016). CACNA1E and epilepsy. Epilepsia 57(10):1610-1619 (2016)](https://doi.org/10.1111/epi.13472)

[Unknown, Bezprozvanny I. (2009). Calcium hypothesis of Alzheimer's disease. Brain Res Rev 61(2):143-148 (2009)](https://doi.org/10.1016/j.brainresrev.2009.06.001)

[Surmeier DJ, et al., (2017). Calcium and parkinson's disease. Nat Rev Neurosci 18(6):325-333 (2017)](https://doi.org/10.1038/nrn.2017.48)

[Saegusa H, et al., (2002). R-type Ca2+ channels in pain signaling. Pain 95(1-2):77-83 (2002)](https://pubmed.ncbi.nlm.nih.gov/11835406/)

[Zamponi GW, et al., (2015). Targeting voltage-gated calcium channels for pain therapy. Nat Rev Drug Discov 14(9):641-658 (2015)](https://doi.org/10.1038/nrd4596)

[Weiss N, et al., (2013). R-type calcium channels: Structure and pharmacology. Channels (Austin) 7(5):333-339 (2013)](https://doi.org/10.4161/chan.26267)

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CACNA1E Protein (Cav2.3 R-type Calcium Channel)

CACNA1E Protein (Cav2.3 R-type Calcium Channel)

Overview

CACNA1E Protein (Cav2.3 R-type Calcium Channel)

Overview

Introduction

Protein Structure and Basic Information

Channel Structure

Alpha-1 Subunit Architecture

Auxiliary Subunits

Physiological Roles

Neuronal Function

Synaptic Transmission

Expression Pattern

Disease Associations

Epilepsy

Alzheimer's Disease

Parkinson's Disease

Chronic Pain

Other Neurological Conditions

Pathogenic Mechanisms

Calcium Dysregulation

Neuronal Hyperexcitability

Synaptic Dysfunction

Therapeutic Implications

Drug Development

Challenges

Key Interactions

Research Methods

Experimental Approaches

Model Systems

Clinical Significance

Genetic Testing

Biomarkers

See Also

External Links

References