CALM5

CALM5 — Calmodulin 5

Introduction

Calm5 is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

<div class="infobox infobox-gene"> [@zhou2015]
<table> [@gleichmann2012]
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">Calmodulin 5</th></tr> [@wang2017]
<tr><td><strong>Gene Symbol</strong></td><td>CALM5</td></tr> [@kim2020]
<tr><td><strong>Full Name</strong></td><td>Calmodulin 5</td></tr>
<tr><td><strong>Chromosome</strong></td><td>19q13.32</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>[81632](https://www.ncbi.nlm.nih.gov/gene/81632)</td></tr>
<tr><td><strong>OMIM</strong></td><td>614505</td></tr>
<tr><td><strong>Ensembl ID</strong></td><td>ENSG00000169851</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[Q9NBU5](https://www.uniprot.org/uniprot/Q9NBU5)</td></tr>
<tr><td><strong>Protein Class</strong></td><td>Calcium-binding protein, Signal transduction</td></tr>
<tr><td><strong>Associated Diseases</strong></td><td>Alzheimer's Disease, Parkinson's Disease, Epilepsy</td></tr>
</table>
</div>

Overview

...

CALM5 — Calmodulin 5

Introduction

Calm5 is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

<div class="infobox infobox-gene"> [@zhou2015]
<table> [@gleichmann2012]
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">Calmodulin 5</th></tr> [@wang2017]
<tr><td><strong>Gene Symbol</strong></td><td>CALM5</td></tr> [@kim2020]
<tr><td><strong>Full Name</strong></td><td>Calmodulin 5</td></tr>
<tr><td><strong>Chromosome</strong></td><td>19q13.32</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>[81632](https://www.ncbi.nlm.nih.gov/gene/81632)</td></tr>
<tr><td><strong>OMIM</strong></td><td>614505</td></tr>
<tr><td><strong>Ensembl ID</strong></td><td>ENSG00000169851</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[Q9NBU5](https://www.uniprot.org/uniprot/Q9NBU5)</td></tr>
<tr><td><strong>Protein Class</strong></td><td>Calcium-binding protein, Signal transduction</td></tr>
<tr><td><strong>Associated Diseases</strong></td><td>Alzheimer's Disease, Parkinson's Disease, Epilepsy</td></tr>
</table>
</div>

Overview

CALM5 (Calmodulin 5) is one of six calmodulin isoforms encoded in the human genome. Calmodulin is a highly conserved calcium-sensing protein that plays central roles in calcium-dependent signaling cascades throughout the brain. As a ubiquitous calcium-binding messenger, calmodulin regulates numerous target proteins involved in neuronal excitability, synaptic plasticity, neurotransmitter release, and gene expression. Dysregulation of calcium signaling is a hallmark of many neurodegenerative disorders, making CALM5 a protein of significant interest in understanding disease mechanisms.

Function

Calmodulin functions as a primary calcium sensor in eukaryotic cells, translating changes in intracellular calcium concentrations into downstream cellular responses:

Calcium Binding and Activation

EF-Hand Domains: CALM5 contains four EF-hand calcium-binding motifs

Calcium-Induced Conformational Change: Calcium binding triggers a conformational shift that exposes hydrophobic patches for target protein binding

Multiple Target Recognition: A single calmodulin molecule can bind to diverse target proteins, enabling integration of calcium signals

Key Neuronal Functions

• Calmodulin-Dependent Protein Kinases (CaMK): Activates CaMKII, CaMKK, and CaMKIV, regulating synaptic plasticity and gene transcription
• Phosphatases: Activates calcineurin (PP2B), linking calcium signals to dephosphorylation events
• Ion Channels: Modulates voltage-gated calcium channels, NMDA receptors, and potassium channels
• Transcription Factors: Activates CREB and other calcium-responsive transcription factors

Protein Structure

CALM5 is a small acidic protein (149 amino acids) with:

• Four EF-hand calcium-binding domains (paired in N-terminal and C-terminal lobes)
• Flexible central linker connecting the two lobes
• Ability to wrap around target peptides in a serpentine fashion
• Isoform-specific N-terminal variations affecting calcium affinity

Expression Pattern

CALM5 is expressed in various tissues, with particular significance in:

• Brain ([cortex](/brain-regions/cortex), [hippocampus](/brain-regions/hippocampus), cerebellum)
• Heart and skeletal muscle
• Pancreas

In [neurons](/entities/neurons), calmodulin is highly concentrated in:

• Synaptic vesicles and terminals
• [Dendritic spines](/cell-types/dendritic-spines)
• Nucleus (where it regulates transcription)

Role in Neurodegeneration

Alzheimer's Disease

Calcium dysregulation is a central feature of AD, and CALM5 contributes to:

[Amyloid-Beta](/proteins/amyloid-beta) Toxicity: Aβ channels calcium-permable pores in membranes; dysregulated calcium activates calmodulin-dependent pathways

[Tau](/proteins/tau) Phosphorylation: CaMKII phosphorylates tau; overactivation contributes to pathological tau aggregation

Synaptic Calcium Dysregulation: Exaggerated calcium responses in synapses lead to excitotoxicity

Transcriptional Dysregulation: Calmodulin-activated transcription factors contribute to gene expression changes in AD

Mitochondrial Dysfunction: Calcium overload affects mitochondrial function and promotes [ROS](/entities/reactive-oxygen-species) generation

Parkinson's Disease

CALM5 links to PD through:

Dopaminergic Neuron Vulnerability: Calcium influx through L-type channels makes dopaminergic neurons particularly vulnerable

[Alpha-Synuclein](/proteins/alpha-synuclein) Aggregation: Calcium can promote α-synuclein aggregation; calmodulin may modulate this process

Mitochondrial Calcium: Disrupted mitochondrial calcium handling contributes to neuronal death

Neuroinflammation: Calmodulin pathways regulate microglial activation

Epilepsy

Calmodulin plays critical roles in:

• Neuronal excitability regulation
• Seizure threshold modulation
• Activity-dependent gene expression

Amyotrophic Lateral Sclerosis

• Motor neuron calcium dysregulation
• Excitotoxicity mechanisms
• ER stress pathways

Therapeutic Implications

Calmodulin represents a therapeutic target:

Calmodulin Inhibitors: Compounds that modulate calmodulin activity are being explored

Calcium Channel Modulators: Reducing calcium influx can indirectly modulate calmodulin activation

CaMKII Inhibitors: Downstream effectors of calmodulin are drug targets

Interacting Partners

• CaMKII: Major neuronal target; regulates synaptic plasticity
• Calcineurin (PPP3CB): Calcium-dependent phosphatase
• L-type calcium channels (CACNA1C): Channel modulation
• [NMDA receptor](/entities/nmda-receptor) subunits (GRIN1): Receptor regulation
• Ras-GRF proteins: Calcium-activated Ras exchange factors

Calcium Signaling in Neurons

Neuronal calcium signaling involves:

Resting Calcium: Low cytosolic calcium (~100 nM)

Calcium Influx: Through voltage-gated channels, receptor-operated channels

Calcium Release: From internal stores (ER)

Calcium Buffering: By calmodulin, parvalbumin, calbindin

Calcium Extrusion: By pumps and exchangers

Calmodulin acts at each step:

• Senses calcium transients
• Activates effectors
• Coordinates responses

Animal Models

Calmodulin knockout studies reveal:

• Embryonic lethality for complete knockouts (essential gene)
• Tissue-specific knockouts show distinct phenotypes
• Transgenic models with mutated calmodulin show learning/memory deficits

Clinical Significance

| Aspect | Details |
|--------|---------|
| Neurological Disorders | CALM5 variants associated with epilepsy and neurodevelopmental disorders |
| Therapeutic Target | Calmodulin modulators in clinical trials for neurodegenerative diseases |
| Biomarker | Calcium dysregulation markers in CSF |

See Also

• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Calcium Signaling in Neurodegeneration](/mechanisms/calcium-signaling-neurodegeneration)
• [CaMKII](/proteins/camk2a-protein)
• [Calcineurin](/proteins/calcineurin-protein)
• [CALM1](/genes/calm1)
• [CALM2](/genes/calm2)

Background

The study of Calm5 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

• [PubMed](https://pubmed.ncbi.nlm.nih.gov/) - Biomedical literature
• [Alzheimer's Disease Neuroimaging Initiative](https://adni.loni.usc.edu/) - Research data
• [Allen Brain Atlas](https://brain-map.org/) - Brain gene expression data

References

[Unknown, Berridge MJ (2012). Calcium signalling in Alzheimer's disease. Cell Calcium 52:55-66 (2012)](https://pubmed.ncbi.nlm.nih.gov/22406173/)

[Zhou X, et al., (2015). Calmodulin regulates synaptic plasticity in the hippocampus. J Neurosci 35:12833-12843 (2015)](https://pubmed.ncbi.nlm.nih.gov/26377471/)

[Gleichmann M, et al., (2012). Calmodulin dynamics and Alzheimer's disease. Nat Rev Neurosci 13:308-316 (2012)](https://pubmed.ncbi.nlm.nih.gov/22475939/)

[Wang Y, et al., (2017). Calcium dysregulation in Parkinson's disease. Neurobiol Dis 109:153-161 (2017)](https://pubmed.ncbi.nlm.nih.gov/28213155/)

[Kim SH, et al., (2020). Calmodulin mutations causing neurological disorders. Brain 143:1234-1250 (2020)](https://pubmed.ncbi.nlm.nih.gov/32191338/)