Cacna1C Gene is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
{{infobox gene
| name = Calcium Voltage-Gated Channel Alpha Subunit 1C
| symbol = CACNA1C
| chromosomal_location = 12p13.32
| ncbi_gene_id = 775
| ensembl_id = ENSG00000132938
| uniprot_id = Q13936
| omim_id = 114205
| associated_diseases = Timothy Syndrome, Bipolar Disorder, Schizophrenia, Alzheimer's Disease, Parkinson's Disease
}}
CACNA1C encodes the alpha-1C subunit of the L-type voltage-gated calcium channel (Cav1.2), one of the most important calcium channels in neurons and cardiac myocytes. This channel plays critical roles in synaptic plasticity, gene transcription, and cellular excitability.
Cav1.2 is an L-type voltage-gated calcium channel with several key characteristics:
- Channel Type: L-type calcium channel (Cav1.2)
- Primary Structure: Alpha-1 subunit with 4 repeat domains, each containing 6 transmembrane segments
- Biophysical Properties: High voltage activation, slow inactivation, dihydropyridine-sensitive
- Subcellular Localization: Somatodendritic compartment, dendritic spines, cardiac cells
- Synaptic Plasticity: Couples synaptic activity to gene transcription via Ca2+-dependent signaling
- Dendritic Spine Function: Regulates calcium influx in dendritic spines during LTP and LTD
- Transcriptional Regulation: Activates CREB and other transcription factors
- neuronal Development: Critical for dendritic growth and synapse formation
- Causative gene for Timothy syndrome, a multisystem disorder
- Gain-of-function missense mutations (e.g., G406R) cause prolonged channel opening
- Associated with cardiac arrhythmias, autism, seizures
- Genome-wide significant association with bipolar disorder, schizophrenia, and major depressive disorder
- Risk SNPs in intronic regions affect gene expression and splicing
- May affect neuronal calcium signaling and synaptic plasticity
- Altered Cav1.2 function affects calcium homeostasis in neurons
- Involved in amyloid-beta-induced synaptic dysfunction
- Therapeutic target for calcium dysregulation in AD
- Cav1.2 channels regulate dopaminergic neuron function
- L-type channel blockers may protect dopaminergic neurons
- Altered expression in PD brain regions
- Brain: High expression in cortex, hippocampus, basal ganglia, cerebellum
- Heart: Cardiac muscle (ventricles, atria)
- Other Tissues: Smooth muscle, endocrine cells, fibroblasts
- Dihydropyridines: Nimodipine, amlodipine (blood-brain barrier penetrant: nimodipine)
- Benzothiazepines: Diltiazem
- Phenylalkylamines: Verapamil
- Clinical Trials: L-type channel blockers being investigated for neuroprotection in AD and PD
- Splawski I, et al. (2004). Ca(V)1.2 calcium channel dysfunction causes cardiac and neurological disease. Nat Med.
- Bialer M, et al. (2019). CACNA1C in neuropsychiatric disorders. Nat Rev Neurosci.
- Muller HK, et al. (2020). L-type calcium channels in Alzheimer's disease. Mol Neurobiol.
The study of Cacna1C Gene has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
[1] Splawski I, et al. (2004). Ca(V)1.2 calcium channel dysfunction causes cardiac and neurological disease. Nat Med.
[2] Bialer M, et al. (2019). CACNA1C in neuropsychiatric disorders. Nat Rev Neurosci.
[3] Muller HK, et al. (2020). L-type calcium channels in Alzheimer's disease. Mol Neurobiol.
Cav1.2 channels are composed of:
- α1C subunit (CACNA1C): Forms the calcium-permeable pore
- β subunits (β1-β4): Modulate trafficking and gating
- α2δ subunits (α2δ1-4): Assist in channel assembly
- γ subunits: Tissue-specific modulators
- Activation threshold: ∼-40 mV
- Activation kinetics: Relatively slow compared to other VGCCs
- Inactivation: Both voltage-dependent and calcium-dependent (CDI)
- Recovery: Slow recovery from inactivation
Cav1.2 channels undergo CDI, a unique feature:
- Calcium influx through the channel activates calmodulin
- Calmodulin binds to the C-terminal tail
- This triggers channel closure even during continued depolarization
- Protein kinase CK2 and CaMKII modulate CDI strength
PKA phosphorylation of Cav1.2:
- Increases channel open probability
- Enhances L-type current amplitude
- Critical for β-adrenergic regulation of cardiac function
- Dysregulation linked to neuropsychiatric disorders
| Drug |
Use |
Mechanism |
| Amlodipine |
Hypertension, angina |
L-type block |
| Nifedipine |
Hypertension |
L-type block |
| Verapamil |
Arrhythmia, migraine |
L-type block |
| Nimodipine |
Subarachnoid hemorrhage |
L-type block (CNS selective) |
| Isradipine |
Parkinson's disease |
Neuroprotection |
- Isradipine: Under investigation for PD neuroprotection
- DKK1 inhibitors: Targeting Cav1.2 channel regulation
- Allosteric modulators: Preferring brain isoform
- CACNA1C knockout: Embryonic lethal (cardiac requirements)
- Conditional KO: Brain-specific deletion shows cognitive deficits
- Mutant mice: Timothy syndrome model shows autism-like behaviors
- Isoform-selective blockers for CNS disorders
- Gene therapy approaches for channelopathies
- Understanding isoform-specific functions in brain