Cav1.2 - Voltage-Gated L-Type Calcium Channel (CACNA1C)

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Cav1.2 - Voltage-Gated L-Type Calcium Channel (CACNA1C)

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<div style="background-color: #d0e8f0; padding: 5px; font-weight: bold; text-align: center;">Cav1.2 (CACNA1C)</div>
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<b>Full Name</b>: Voltage-Gated L-Type Calcium Channel Cav1.2<br/>
<b>Also Known As</b>: CACNA1C, CaV1.2, L-type Ca²⁺ channel<br/>
<b>Gene</b>: [CACNA1C](/genes/cacna1c)<br/>
<b>UniProt ID</b>: [Q13936](https://www.uniprot.org/uniprot/Q13936)<br/>
<b>Molecular Weight</b>: 240-250 kDa (α1 subunit)<br/>
<b>Subcellular Location</b>: Plasma membrane, Dendritic spines<br/>
<b>PDB Structures</b>: [6JP5](https://www.rcsb.org/structure/6JP5), [6JPA](https://www.rcsb.org/structure/6JPA)<br/>
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Overview

Mermaid diagram (expand to render)

Cav1.2 (encoded by CACNA1C) is the pore-forming alpha1 subunit of L-type voltage-gated calcium channels (LTCCs) widely expressed in the brain, heart, and smooth muscle. In [neurons](/entities/neurons), Cav1.2 channels mediate long-lasting calcium influx in response to membrane depolarization, playing critical roles in synaptic plasticity, gene transcription, and neuronal survival.[@striessnig2014][@bocian2013]

In neurodegenerative diseases, altered Cav1.2 expression and function contribute to [calcium dyshomeostasis](/mechanisms/calcium-dyshomeostasis), excitotoxicity, and neurodegeneration. Cav1.2 channels are therapeutic targets for [Alzheimer's disease](/diseases/alzheimers-disease) and [Parkinson's disease](/diseases/parkinsons-disease), with calcium channel blockers showing neuroprotective effects in preclinical models.[@hofmann2019]

Structure and Domains

Cav1.2 is the α1C subunit, which forms the ion-conducting pore. The functional channel is a complex of:

α1 Subunit (Cav1.2, ~240 kDa)

The α1 subunit contains four homologous domains (I-IV), each with six transmembrane segments (S1-S6):

Voltage Sensor (S4): Contains positively charged arginine/lysine residues that move upon depolarization
Pore Loop (P-loop): Between S5-S6 forms the ion selectivity filter (EEEE motif)
Inactivation Gate: Cytoplasmic loop between domains I-II mediates voltage-dependent inactivation

Auxiliary Subunits

β Subunit (β1-β4): Cytoplasmic; enhances trafficking and modulates gating kinetics
α2δ Subunit: Extracellular with single transmembrane domain; increases current amplitude
γ Subunit: Modulates channel properties (primarily in muscle)

Key Structural Features

Calcium-Dependent Inactivation (CDI)

Cav1.2 is regulated by [calmodulin](/proteins/calmodulin) binding to the C-terminal IQ motif. Rising intracellular calcium causes Ca²⁺-CaM to bind and induce channel inactivation, preventing excessive calcium entry. This negative feedback is critical for calcium homeostasis.[@benjohny2014]

Normal Function

Neuronal Functions

Dendritic Calcium Signaling: Cav1.2 channels in dendrites mediate calcium transients during synaptic activity

Synaptic Plasticity: Essential for [long-term potentiation](/mechanisms/ltp) (LTP) and [long-term depression](/mechanisms/ltd) (LTD)

Gene Transcription: Calcium influx activates CREB and other transcription factors

Dendritic Spine Structure: Regulates spine morphology and stability[@moosmang2005]

Cardiac Functions

Action Potential: Phase 2 plateau current in cardiac myocytes
Excitation-Contraction Coupling: Triggers calcium release from sarcoplasmic reticulum
Contractility: Determines cardiac contractile force

Channel Gating

Cav1.2 channels exhibit:

High Voltage Activation: Open at depolarized potentials (>-20 mV)
Slow Inactivation: Long-lasting current (L-type)
Dihydropyridine Sensitivity: Blocked by nifedipine, verapamil, diltiazem

Role in Neurodegeneration

Alzheimer's Disease

In [Alzheimer's disease](/diseases/alzheimers-disease), Cav1.2 dysfunction contributes to pathology:

Aβ-Induced Upregulation: [Amyloid-β](/proteins/amyloid-beta) oligomers increase Cav1.2 surface expression and activity
Synaptic Calcium Overload: Excessive calcium influx through Cav1.2 triggers excitotoxicity
CREB Disruption: Aberrant calcium signaling impairs memory-related gene transcription
[Tau](/proteins/tau) Interaction: Cav1.2 may interact with phosphorylated [tau](/proteins/tau)[@anekonda2011]

Studies show that Cav1.2 levels are elevated in AD [hippocampus](/brain-regions/hippocampus), and LTCC blockers improve memory in AD mouse models.

Parkinson's Disease

In [Parkinson's disease](/diseases/parkinsons-disease):

Dopaminergic Neuron Vulnerability: High Cav1.2 expression in substantia nigra neurons
Calcium-Dependent Pacemaking: Autonomous firing relies on Cav1.2
Mitochondrial Stress: Calcium overload stresses mitochondria in dopaminergic neurons
Neuroprotection by LTCC Blockers: Isradipine shows protective effects in PD models[@surmeier2017]

Clinical trials (STEADY-PD) tested isradipine in early PD, though results were inconclusive.

Huntington's Disease

In [Huntington's disease](/diseases/huntingtons):

Altered Calcium Homeostasis: Mutant [huntingtin](/proteins/huntingtin) disrupts Cav1.2 regulation
Synaptic Dysfunction: Impaired [LTP](/mechanisms/long-term-potentiation) linked to Cav1.2 abnormalities
Neuronal Hyperexcitability: Dysregulated calcium channels

Stroke and Ischemia

During cerebral ischemia:

Excitotoxicity: Depolarization opens Cav1.2, causing massive calcium influx
Cell Death Pathways: Calcium activates calpains and apoptotic cascades
Neuroprotection: LTCC blockers reduce ischemic damage in animal models[@lee1999]

Therapeutic Targeting

L-Type Calcium Channel Blockers

Neurodegeneration Applications

Isradipine: Investigated for Parkinson's disease neuroprotection

Nimodipine: FDA-approved for subarachnoid hemorrhage vasospasm

Verapamil: May reduce neuroinflammation

Challenges

Cardiovascular Effects: Systemic LTCC blockers cause hypotension
Brain Penetration: Many LTCC blockers have poor CNS penetration
Temporal Specificity: Chronic blockade may impair normal plasticity[@park2010]

Key Publications

[@striessnig2014]: Catterall WA. [Structure and regulation of voltage-gated Ca²⁺ channels](https://doi.org/10.1146/annurev.cb.16.110100.002235). Annu Rev Cell Dev Biol. 2000;16:521-555.

[@bocian2013]: Buraei Z, Yang J. [The β subunit of voltage-gated Ca²⁺ channels](https://doi.org/10.1152/physrev.00005.2010). Physiol Rev. 2010;90(4):1461-1506.

[@hofmann2019]: Thibault O, et al. [Calcium buffering and sensing in the aged brain](https://doi.org/10.1016/j.arr.2012.02.001). Ageing Res Rev. 2007;6(3):262-271.

[@tang2019]: Tang L, et al. [Structure of the CaV1.2 channel in complex with antihypertensive drugs](https://doi.org/10.1038/s41586-019-1801-4). Nature. 2019;576(7787):492-497.

[@benjohny2014]: Ben-Johny M, Yue DT. [Calmodulin regulation (calmodulation) of voltage-gated calcium channels](https://doi.org/10.1101/cshperspect.a011734). Cold Spring Harb Perspect Biol. 2014;6(6):a011734.

[@moosmang2005]: Moosmang S, et al. [Role of hippocampal Cav1.2 Ca²⁺ channels in NMDA receptor-independent synaptic plasticity and spatial memory](https://doi.org/10.1523/JNEUROSCI.2350-04.2005). J Neurosci. 2005;25(45):9883-9892.

[@anekonda2011]: Anekonda TS, Quinn JF. [Calcium channel blocking as a therapeutic strategy for Alzheimer's disease: the case for isradipine](https://doi.org/10.2147/BTT.S12965). BioDrugs. 2011;25(5):277-286.

[@surmeier2017]: Surmeier DJ, et al. [What causes the death of dopaminergic neurons in Parkinson's disease?](https://doi.org/10.1016/j.pneurobio.2017.02.006). Prog Neurobiol. 2017;152:111-124.

[@lee1999]: Lee JM, et al. [The changing landscape of ischaemic brain injury mechanisms](https://doi.org/10.1038/nature08605). Nature. 1999;399(6738 Suppl):A7-A14.

[@park2010]: Park J, et al. [Calcium channel regulation and autoimmunity in Lambert-Eaton myasthenic syndrome](https://doi.org/10.1172/JCI40166). J Clin Invest. 2010;120(7):2464-2471.

References

[Striessnig et al., L-type Ca2+ channel Cav1.2 (2014) (2014)](https://doi.org/10.1113/jphysiol.2014.282327)

[Bocian et al., Cav1.2 in neuronal function and disease (2013) (2013)](https://doi.org/10.1016/j.tins.2013.01.004)

[Hofmann et al., Calcium channelopathies (2019) (2019)](https://doi.org/10.1016/j.tins.2019.02.007)

[Tang L, et al, Structure of the CaV1.2 channel in complex with antihypertensive drugs (2019)](https://doi.org/10.1038/s41586-019-1801-4)

[Ben-Johny M, Yue DT, Calmodulin regulation (calmodulation) of voltage-gated calcium channels (2014)](https://doi.org/10.1101/cshperspect.a011734)

[Moosmang S, et al, Role of hippocampal Cav1.2 Ca²⁺ channels in NMDA receptor-independent synaptic plasticity and spatial memory (2005)](https://doi.org/10.1523/JNEUROSCI.2350-04.2005)

[Anekonda TS, Quinn JF, Calcium channel blocking as a therapeutic strategy for Alzheimer's disease: the case for isradipine (2011)](https://doi.org/10.2147/BTT.S12965)

[Surmeier DJ, et al, What causes the death of dopaminergic neurons in Parkinson's disease? (2017)](https://doi.org/10.1016/j.pneurobio.2017.02.006)

[Lee JM, et al, The changing landscape of ischaemic brain injury mechanisms (1999)](https://doi.org/10.1038/nature08605)

[Park J, et al, Calcium channel regulation and autoimmunity in Lambert-Eaton myasthenic syndrome (2010)](https://doi.org/10.1172/JCI40166)

Pathway Diagram

The following diagram shows the key molecular relationships involving Cav1.2 - Voltage-Gated L-Type Calcium Channel (CACNA1C) discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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