Cav1.2 Protein (L-type Calcium Channel Alpha-1C)

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Cav1.2 Protein (L-type Calcium Channel Alpha-1C)

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Cav1.2 Protein (L-type Calcium Channel Alpha-1C)

Introduction

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Cav1.2 Protein (L-type Calcium Channel Alpha-1C)</th>
</tr>
<tr>
<td class="label">Subunit</td>
<td>Gene</td>
</tr>
<tr>
<td class="label">α1C</td>
<td>CACNA1C</td>
</tr>
<tr>
<td class="label">β1-4</td>
<td>CACNB1-4</td>
</tr>
<tr>
<td class="label">α2δ1-4</td>
<td>CACNA2D1-4</td>
</tr>
<tr>
<td class="label">γ1-8</td>
<td>CACNG1-8</td>
</tr>
<tr>
<td class="label">Drug</td>
<td>Type</td>
</tr>
<tr>
<td class="label">Nimodipine</td>
<td>Dihydropyridine</td>
</tr>
<tr>
<td class="label">Isradipine</td>
<td>Dihydropyridine</td>
</tr>
<tr>
<td class="label">Amlodipine</td>
<td>Dihydropyridine</td>
</tr>
<tr>
<td class="label">Verapamil</td>
<td>Phenylalkylamine</td>
</tr>
<tr>
<td class="label">Diltiazem</td>
<td>Benzothiazepine</td>
</tr>
<tr>
<td class="label">Biomarker</td>
<td>Sample</td>
</tr>
<tr>
<td class="label">CACNA1C expression</td>
<td>Brain tissue</td>
</tr>
<tr>
<td class="label">L-type calcium current</td>
<td>Neuronal models</td>
</tr>
<tr>
<td class="label">CaMKII activation</td>
<td>Brain tissue</td>
</tr>
<tr>
<td class="label">Nuclear calcium</td>
<td>Cellular models</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzhei

...

Cav1.2 Protein (L-type Calcium Channel Alpha-1C)

Introduction

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Cav1.2 Protein (L-type Calcium Channel Alpha-1C)</th>
</tr>
<tr>
<td class="label">Subunit</td>
<td>Gene</td>
</tr>
<tr>
<td class="label">α1C</td>
<td>CACNA1C</td>
</tr>
<tr>
<td class="label">β1-4</td>
<td>CACNB1-4</td>
</tr>
<tr>
<td class="label">α2δ1-4</td>
<td>CACNA2D1-4</td>
</tr>
<tr>
<td class="label">γ1-8</td>
<td>CACNG1-8</td>
</tr>
<tr>
<td class="label">Drug</td>
<td>Type</td>
</tr>
<tr>
<td class="label">Nimodipine</td>
<td>Dihydropyridine</td>
</tr>
<tr>
<td class="label">Isradipine</td>
<td>Dihydropyridine</td>
</tr>
<tr>
<td class="label">Amlodipine</td>
<td>Dihydropyridine</td>
</tr>
<tr>
<td class="label">Verapamil</td>
<td>Phenylalkylamine</td>
</tr>
<tr>
<td class="label">Diltiazem</td>
<td>Benzothiazepine</td>
</tr>
<tr>
<td class="label">Biomarker</td>
<td>Sample</td>
</tr>
<tr>
<td class="label">CACNA1C expression</td>
<td>Brain tissue</td>
</tr>
<tr>
<td class="label">L-type calcium current</td>
<td>Neuronal models</td>
</tr>
<tr>
<td class="label">CaMKII activation</td>
<td>Brain tissue</td>
</tr>
<tr>
<td class="label">Nuclear calcium</td>
<td>Cellular models</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/anxiety" style="color:#ef9a9a">Anxiety</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/inflammation" style="color:#ef9a9a">Inflammation</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">104 edges</a></td>
</tr>
</table>

Cav1.2 (L-type voltage-gated calcium channel alpha-1C subunit, encoded by CACNA1C) is one of the most important calcium channels in [neurons](/entities/neurons), playing critical roles in calcium-dependent signaling, gene expression regulation, synaptic plasticity, and neuronal survival. Dysregulation of Cav1.2 channels contributes to calcium dysregulation - a central hallmark of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, ALS, and Huntington's disease.

Overview

The Cav1.2 channel is a voltage-gated calcium channel (VGCC) that conducts L-type calcium currents - a sustained, slowly inactivating calcium influx in response to membrane depolarization. In neurons, Cav1.2 channels are located throughout the somatodendritic compartment and contribute to[@ltype2014]:

Calcium-dependent gene transcription
Synaptic plasticity and [LTP](/mechanisms/long-term-potentiation)
Dendritic spike generation
Neurotransmitter release
Neuronal survival signaling
Regulation of neuronal excitability

Cav1.2 channels are unique among VGCCs for their sensitivity to dihydropyridines (e.g., nifedipine, amlodipine) and their role in coupling electrical activity to nuclear calcium signaling[@calcium1998].

The channel's alpha-1C subunit (CACNA1C) is one of the most studied genes in neuropsychiatry, with strong associations to bipolar disorder, schizophrenia, and major depression, underscoring its importance in brain function[@cacnac2013].

Structure

Channel Architecture

Cav1.2 is a heteromultimeric channel complex:

Mermaid diagram (expand to render)

Alpha-1C Subunit

The α1C subunit contains:

Four homologous domains (I-IV), each with 6 transmembrane segments (S1-S6)
Voltage sensor (S4 segment with positively charged residues)
Pore region (S5-S6 loop with selectivity filter)
DHP binding site (in the IVS5-IVS6 region)
C-terminal tail (contains CaM binding sites, PDZ interactions)

Regulatory Domains

Key regulatory sites on α1C:

CaM binding domains (CBD): IQ motif in C-terminus
Phosphorylation sites: Multiple serine/threonine residues
Protein interaction domains: Proline-rich regions, PDZ-binding motif

Splice Variants

Multiple CACNA1C splice variants generate channel isoforms with:

Different gating properties
Altered subcellular localization
Tissue-specific expression
Disease-associated variants

Normal Function

Calcium Influx Mechanisms

Cav1.2 channels open in response to membrane depolarization:

Mermaid diagram (expand to render)

Neuronal Functions

In neurons, Cav1.2 channels mediate [@role2005][@molecular2008]:

Synaptic Plasticity

Required for LTP induction
Regulates AMPA receptor trafficking
Controls spine morphology

Gene Expression

Couples neuronal activity to transcription
Activates CREB-mediated gene expression
Regulates BDNF expression

Dendritic Integration

Generates dendritic calcium spikes
Amplifies synaptic inputs
Controls firing patterns

Neurosecretion

Regulates neurotransmitter release
Controls hormone secretion (in endocrine neurons)
Modulates neuropeptide release

Calcium Signaling Cascades

Downstream of Cav1.2 activation:

Calmodulin activation: Calcium-bound CaM activates multiple enzymes
CaMKII activation: Ca2+/CaM-dependent protein kinase II
Calcineurin activation: Calcium-dependent phosphatase
PKC activation: Protein kinase C
Gene transcription: Via CREB, NFAT, MEF2

Role in Neurodegenerative Diseases

Alzheimer's Disease

Cav1.2 dysfunction in AD includes [@ltype2020][@ltype2019]:

Calcium dysregulation hypothesis: Cav1.2 contributes to AD through:

Enhanced channel activity leading to calcium overload
Increased neuronal vulnerability to Aβ toxicity
Dysregulated calcium-dependent gene expression
Altered synaptic plasticity

Aβ interactions: [Amyloid-beta](/proteins/amyloid-beta):

Directly interacts with voltage-gated calcium channels
Increases channel open probability
Promotes calcium dysregulation
Enhances excitotoxic vulnerability

Therapeutic implications:

L-type calcium channel blockers (CCBs) being studied for AD
Nimodipine trials in AD patients
CCBs may reduce calcium-mediated toxicity

Parkinson's Disease

In PD, Cav1.2 channels contribute to dopaminergic neuron vulnerability [@rejuvenation2007][@calcium2017]:

Pacemaking and calcium overload:

Substantia nigra dopaminergic neurons have unique pacemaking activity
Cav1.2 (particularly Cav1.3) contributes to L-type currents
Continuous calcium influx during pacemaking creates metabolic stress
Calcium dysregulation contributes to mitochondrial dysfunction

[α-Synuclein](/proteins/alpha-synuclein) interactions:

α-Synuclein may modulate calcium channel function
Channel dysfunction enhances α-synuclein toxicity
Calcium dysregulation promotes α-synuclein aggregation

Neuroprotection strategies:

Calcium channel blockers (isradipine) being investigated
Reduces dopaminergic neuron vulnerability

Amyotrophic Lateral SALS

In ALS, Cav1.2 channels [@als2002]:

Motor neuron vulnerability:

Enhanced calcium influx contributes to excitotoxicity
Dysregulated calcium homeostasis in motor neurons
Interaction with ALS-associated proteins (SOD1, FUS, TDP-43)

Therapeutic potential:

Calcium channel modulators may protect motor neurons
Combined with riluzole for potential synergistic effects

Huntington's Disease

In HD, Cav1.2 channels [@calcium2018]:

Dysregulated calcium signaling:

Mutant [huntingtin](/proteins/huntingtin) affects calcium channel function
Enhanced channel activity contributes to excitotoxicity
Altered gene expression patterns

Channel dysfunction:

Dysregulated calcium influx
Impaired synaptic plasticity
Enhanced vulnerability to calcium-dependent cell death

Therapeutic Targeting

Calcium Channel Blockers

Clinical Trials

Several clinical trials are investigating CCBs:

PD: Isradipine phase III trials for neuroprotection
AD: Nimodipine cognitive function studies
ALS: CCB combination therapies

Challenges

Key challenges in targeting Cav1.2:

Peripheral effects: Cardiovascular toxicity limits dosing
[Blood-brain barrier](/entities/blood-brain-barrier): Variable CNS penetration
Channel redundancy: Multiple calcium channel types
Therapeutic window: Balancing efficacy and safety

Biomarkers

Clinical Correlations

Cav1.2 biomarkers may indicate:

Disease progression
Treatment response to CCBs
Calcium dysregulation severity

Cross-Pathway Interactions

Cav1.2 intersects with multiple neurodegenerative pathways [@dysregulation2018]:

Mermaid diagram (expand to render)

Excitotoxicity: Cav1.2 cooperates with NMDA receptors
Mitochondrial calcium: Contributes to mitochondrial dysfunction
Calpain activation: Calcium-dependent protease activation
Gene transcription: Dysregulated expression patterns

Background

The study of Cav1.2 Protein (L Type Calcium Channel Alpha 1C) 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.

External Links

[UniProt Q13936 - CACNA1C](https://www.uniprot.org/uniprot/Q13936)
[CACNA1C Gene - NCBI](https://www.ncbi.nlm.nih.gov/gene/775)
[L-type Calcium Channels - IUPHAR](https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2289)

References

[- Berridge MJ, "Calcium hypothesis of Alzheimer's disease." Nature Reviews Neuroscience (2020)](https://pubmed.ncbi.nlm.nih.gov/32901135/)

[- Surmeier DJ, "Calcium, ageing, and neuronal vulnerability in Parkinson's disease." Nature Reviews Neuroscience (2019)](https://pubmed.ncbi.nlm.nih.gov/28951921/)

[- Striessnig J, Pinggera A, Kaur G, et al, "L-type calcium channels in brain function." Journal of Neurochemistry (2014)](https://pubmed.ncbi.nlm.nih.gov/25252150/)

[- Dolmetsch RE, Xu K, Lewis RS, "Calcium oscillations increase the efficiency and specificity of gene expression." Nature (1998)](https://pubmed.ncbi.nlm.nih.gov/9582075/)

[- Bialer M, Johannessen SI, Levy RH, et al, "CACNA1C and neuropsychiatric disorders." Epilepsia (2013)](https://pubmed.ncbi.nlm.nih.gov/23551225/)

[- Moosmang S, Haider N, Klugbauer N, et al, "Role of L-type Cav1.2 channels in neuronal function." Cellular and Molecular Life Sciences (2005)](https://pubmed.ncbi.nlm.nih.gov/15928695/)

[- Tippens AL, Lee A, "Molecular regulation of neuronal L-type calcium channel function." Current Opinion in Neurobiology (2008)](https://pubmed.ncbi.nlm.nih.gov/18672175/)

[- O'Donnell F, Smigielski MS, Colomar A, et al, "L-type calcium channels and Alzheimer's disease." Neurobiology of Aging (2020)](https://pubmed.ncbi.nlm.nih.gov/31760112/)

[- Wang Y, Mattson MP, "L-type Ca2+ channel signaling in brain." Brain Research (2019)](https://pubmed.ncbi.nlm.nih.gov/30978367/)

[- Chan CS, Guzman JN, Ilijic E, et al, "'Rejuvenation' protects neurons in mouse models of Parkinson's disease." Nature (2007)](https://pubmed.ncbi.nlm.nih.gov/17558391/)

[- Surmeier DJ, Schumacker PT, Guzman JD, et al, "Calcium, mitochondria, and the pathogenesis of PD." Nature Reviews Neurology (2017)](https://pubmed.ncbi.nlm.nih.gov/28257178/)

[- Van Den Bosch L, Van Damme P, Vandesande W, et al, "ALS and calcium." Neuromuscular Disorders (2002)](https://pubmed.ncbi.nlm.nih.gov/11801361/)

[- TWu J, Fan H, Zhang J, et al, "Calcium dysregulation in Huntington's disease." Journal of Huntington's Disease (2018)](https://pubmed.ncbi.nlm.nih.gov/30188497/)

[- Popugaeva E, Pchitskaya E, Bezprozvanny I, "Dysregulation of neuronal calcium signaling in Alzheimer's disease." Cell Calcium (2018)](https://pubmed.ncbi.nlm.nih.gov/28711874/)

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Related Entities

CACNA1CPROTEIN

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slug	proteins-cacna1c-protein
kg_node_id	CACNA1CPROTEIN
entity_type	protein
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-98b15aab7b0e
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-cacna1c-protein'}
_schema_version	1

📊 Evidence Profile Foundational

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📗 Cite This Artifact

Cav1.2 Protein (L-type Calcium Channel Alpha-1C)

Cav1.2 Protein (L-type Calcium Channel Alpha-1C)

Introduction

Cav1.2 Protein (L-type Calcium Channel Alpha-1C)

Introduction

Overview

Structure

Channel Architecture

Alpha-1C Subunit

Regulatory Domains

Splice Variants

Normal Function

Calcium Influx Mechanisms

Neuronal Functions

Calcium Signaling Cascades

Role in Neurodegenerative Diseases

Alzheimer's Disease

Parkinson's Disease

Amyotrophic Lateral SALS

Huntington's Disease

Therapeutic Targeting

Calcium Channel Blockers

Clinical Trials

Challenges

Biomarkers

Clinical Correlations

Cross-Pathway Interactions

Background

See Also

External Links

References

💬 Discussion

📗 Cite This Artifact

Cav1.2 Protein (L-type Calcium Channel Alpha-1C)

Cav1.2 Protein (L-type Calcium Channel Alpha-1C)

Introduction

Cav1.2 Protein (L-type Calcium Channel Alpha-1C)

Introduction

Overview

Structure

Channel Architecture

Alpha-1C Subunit

Regulatory Domains

Splice Variants

Normal Function

Calcium Influx Mechanisms

Neuronal Functions

Calcium Signaling Cascades

Role in Neurodegenerative Diseases

Alzheimer's Disease

Parkinson's Disease

Amyotrophic Lateral SALS

Huntington's Disease

Therapeutic Targeting

Calcium Channel Blockers

Clinical Trials

Challenges

Biomarkers

Cav1.2-Related Biomarkers

Clinical Correlations

Cross-Pathway Interactions

Background

See Also

External Links

References

💬 Discussion