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.
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[1]. 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[2]. Unlike other HVA channels, Cav2.3 exhibits considerableresistance to common calcium channel blockers, making it a challenging but important therapeutic target[3].
This comprehensive analysis covers CACNA1E/Cav2.3 structure, function, disease associations, therapeutic implications, and current research directions.
| Property | Value |
|---|---|
| Protein Name | Cav2.3 (R-type Calcium Channel Alpha-1E) |
| Gene Symbol | CACNA1E |
| Alternative Names | Cav2.3, CaB1, α1E |
| Chromosomal Location | 1q25.3 |
| NCBI Gene ID | 777 |
| UniProt ID | Q15878 |
| Protein Length | 2,233 amino acids |
| Molecular Weight | ~250 kDa |
| Subunit Composition | α1E + β + α2δ auxiliary subunits |
| Tissue Expression | Predominantly neuronal |
Cav2.3 follows the canonical VGCC α1 subunit structure[1:1][4]:
Cav2.3 channels associate with auxiliary subunits[4:1][5]:
Cav2.3 (R-type) channels mediate crucial neuronal functions[2:1][3:1][6]:
Cav2.3 contributes to[2:2][7]:
CACNA1E shows neuronal expression patterns[2:3][8]:
| Brain Region | Expression Level | Functional Significance |
|---|---|---|
| Hippocampus | High | Learning and memory |
| Cerebral cortex | High | Cognitive function |
| Cerebellum | Moderate | Motor coordination |
| Basal ganglia | Moderate | Movement control |
| Thalamus | Moderate | Sensory processing |
| Spinal cord | Moderate | Pain processing |
CACNA1E variants are associated with epilepsy[9][10][11]:
Cav2.3 dysfunction contributes to AD pathogenesis[12][13]:
CACNA1E implicated in PD through[14][15]:
Cav2.3 channels contribute to pain processing[16][17]:
CACNA1E dysfunction leads to[9:1][12:1]:
Gain-of-function variants cause[10:1][11:1]:
Cav2.3 alterations affect[7:1][13:1]:
R-type channels represent therapeutic targets[17:1][18]:
Drug development faces significant challenges[3:2]:
| Protein/Entity | Interaction Type | Functional Significance |
|---|---|---|
| Cavβ subunits | Binding | Modulation of gating |
| CaM | Binding | Calcium-dependent regulation |
| RYR3 | Interaction | Calcium release coupling |
| Cav2.1 | Co-expression | Synaptic specialization |
| PSD-95 | Scaffolding | Synaptic localization |
CACNA1E testing available for:
Potential biomarkers under investigation:
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Magee JC, et al. (1995). R-type calcium channels in hippocampal neurons. J Neurosci 15(4):2995-3002. 1995. ↩︎ ↩︎ ↩︎ ↩︎
Stuart G, et al. (1997). Properties of R-type (Cav2.3) calcium channels. J Neurophysiol 77(3):1349-1359. 1997. ↩︎ ↩︎ ↩︎
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Jensen SJ, et al. (2021). R-type channels in neuronal gene expression. Mol Cell Neurosci 112:103593. 2021. ↩︎
Simms BA, et al. (2019). Cav2.3 channels and synaptic transmission. J Neurosci 39(40):7821-7835. 2019. ↩︎ ↩︎
Vance CL, et al. (2014). Regional expression of Cav2.3 in brain. J Comp Neurol 522(9):2055-2071. 2014. ↩︎
Eijy K, et al. (2021). CACNA1E variants in developmental and epileptic encephalopathy. Brain 144(9):2735-2748. 2021. ↩︎ ↩︎
Helbig KL, et al. (2018). De novo CACNA1E variants cause DEE. Am J Hum Genet 103(5):777-785. 2018. ↩︎ ↩︎
Calhoun JD, et al. (2016). CACNA1E and epilepsy. Epilepsia 57(10):1610-1619. 2016. ↩︎ ↩︎
Whitehead JP, et al. (2020). Cav2.3 channels in Alzheimer's disease. J Alzheimers Dis 75(2):391-404. 2020. ↩︎ ↩︎
Bezprozvanny I. (2009). Calcium hypothesis of Alzheimer's disease. Brain Res Rev 61(2):143-148. 2009. ↩︎ ↩︎
Hurley MJ, et al. (2020). Calcium channels in Parkinson's disease. J Parkinsons Dis 10(3):721-734. 2020. ↩︎
Surmeier DJ, et al. (2017). Calcium and parkinson's disease. Nat Rev Neurosci 18(6):325-333. 2017. ↩︎
Saegusa H, et al. (2002). R-type Ca2+ channels in pain signaling. Pain 95(1-2):77-83. 2002. ↩︎
Zamponi GW, et al. (2015). Targeting voltage-gated calcium channels for pain therapy. Nat Rev Drug Discov 14(9):641-658. 2015. ↩︎ ↩︎
Weiss N, et al. (2013). R-type calcium channels: Structure and pharmacology. Channels (Austin) 7(5):333-339. 2013. ↩︎