CALCA (Calcitonin Alpha)
Introduction
flowchart TD
CALCA["CALCA"] -->|"inhibits"| Ptsd["Ptsd"]
CALCA["CALCA"] -->|"inhibits"| Ms["Ms"]
CALCA["CALCA"] -->|"inhibits"| BDNF["BDNF"]
CALCA["CALCA"] -->|"associated with"| IL18["IL18"]
CALCA["CALCA"] -->|"inhibits"| NR3C1["NR3C1"]
CALCA["CALCA"] -->|"inhibits"| FKBP5["FKBP5"]
CALCA["CALCA"] -->|"associated with"| RAMP1["RAMP1"]
CALCA["CALCA"] -->|"inhibits"| CRH["CRH"]
CALCA["CALCA"] -->|"associated with"| IL18BP["IL18BP"]
CALCA["CALCA"] -->|"inhibits"| CRHR1["CRHR1"]
CALCA["CALCA"] -->|"interacts with"| IL18["IL18"]
CALCA["CALCA"] -->|"interacts with"| IL18BP["IL18BP"]
CALCA["CALCA"] -->|"interacts with"| RAMP1["RAMP1"]
CALCA["CALCA"] -->|"inhibits"| Rb["Rb"]
style CALCA fill:#4fc3f7,stroke:#333,color:#000
CALCA (Calcitonin Alpha) is a gene that encodes both calcitonin and alpha-CGRP (Calcitonin Gene-Related Peptide) through alternative RNA splicing. This gene is crucial in neurobiology, with implications in pain transmission, neuroinflammation, vasodilation, and increasingly recognized roles in neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's disease (PD). [@ramanathan2024]
...CALCA (Calcitonin Alpha)
Introduction
Mermaid diagram (expand to render)
CALCA (Calcitonin Alpha) is a gene that encodes both calcitonin and alpha-CGRP (Calcitonin Gene-Related Peptide) through alternative RNA splicing. This gene is crucial in neurobiology, with implications in pain transmission, neuroinflammation, vasodilation, and increasingly recognized roles in neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's disease (PD). [@ramanathan2024]
<div class="infobox infobox-gene">
<table>
<tr><th>Gene Symbol</th><td>CALCA</td></tr>
<tr><th>Full Name</th><td>Calcitonin Alpha</td></tr>
<tr><th>Chromosomal Location</th><td>11p15.2</td></tr>
<tr><th>NCBI Gene ID</th><td>[796](https://www.ncbi.nlm.nih.gov/gene/796)</td></tr>
<tr><th>OMIM</th><td>[114090](https://www.omim.org/entry/114090)</td></tr>
<tr><th>Ensembl ID</th><td>ENSG00000110680</td></tr>
<tr><th>UniProt ID</th><td>[P01258](https://www.uniprot.org/uniprot/P01258)</td></tr>
<tr><th>Associated Diseases</th><td>[Migraine](/diseases/migraine), [Alzheimer's Disease](/diseases/alzheimers-disease), [Stroke](/diseases/stroke)</td></tr>
</table>
</div>
Gene Structure and Processing
The CALCA gene consists of 6 exons and undergoes alternative splicing to produce distinct mRNAs encoding:
- Calcitonin: A 32-amino acid hormone involved in calcium homeostasis
- α-CGRP: The predominant neuropeptide form in the nervous system
- Katacalcin: A shorter peptide with uncertain function
The tissue-specific expression pattern is determined by alternative promoter usage and RNA processing, with neurons primarily generating CGRP transcripts while thyroid C-cells produce calcitonin. [@schou2020]
Molecular Function
Alternative Splicing
The CALCA gene produces two distinct peptide hormones through tissue-specific alternative splicing:
- Calcitonin: A 32-amino acid peptide hormone primarily involved in calcium homeostasis, secreted by thyroid C-cells
- α-CGRP (Calcitonin Gene-Related Peptide): A 37-amino acid neuropeptide with widespread distribution in the nervous system
α-CGRP Signaling
α-CGRP is one of the most abundant neuropeptides in the peripheral and central nervous systems. It signals through two receptor types:
- CLR/RAMP1 receptor: The canonical CGRP receptor
- CLR/RAMP2 or RAMP3 receptors: Associated with AM (adrenomedullin) receptors
CGRP binding triggers:
- G protein-coupled receptor signaling
- Increased cAMP production
- Activation of PKA pathway
- Modulation of ion channel activity
Normal Function
Pain Transmission
CGRP is extensively involved in nociceptive signaling within the trigeminovascular system, which is central to migraine pathophysiology. It acts as a neuropeptide transmitter in primary sensory neurons (Aδ and C fibers) and modulates pain signals at both peripheral and central terminals. CGRP does not directly induce pain but sensitizes nociceptors and promotes neurogenic inflammation.
Vasodilation
As a potent vasodilator, CGRP acts on CGRP1 receptors (CLR/RAMP1 complex) on vascular smooth muscle cells, triggering cAMP-mediated relaxation. This vasodilatory effect is particularly prominent in the cerebral and meningeal vasculature, making CGRP a key mediator of migraine-associated blood flow changes.
Neuroinflammation
CGRP exhibits complex immunomodulatory properties:
- Pro-inflammatory: Promotes mast cell degranulation and cytokine release
- Anti-inflammatory: May inhibit T-cell activation in some contexts
- Neuroimmune modulation: Coordinates communication between neurons and immune cells
The balance of these effects appears context-dependent, with dysregulated CGRP signaling contributing to chronic neuroinflammatory states. [@ramanathan2024]
Expression Pattern
CALCA is expressed in:
- Dorsal root ganglion (primary sensory neurons)
- Trigeminal ganglion (cranial nociceptors)
- Central nervous system: cortex, thalamus, hypothalamus
- Cardiovascular system: perivascular nerves, heart
- Endocrine cells: thyroid C-cells, adrenal medulla
Within the brain, CGRP is found in both neuronal cell bodies and synaptic terminals, where it acts as a neurotransmitter or neuromodulator.
Disease Associations
Migraine
CGRP is central to migraine pathophysiology:
- Elevated CGRP levels during migraine attacks
- CGRP triggers migraine episodes
- Therapeutic targets: CGRP receptor antagonists (gepants) and monoclonal antibodies against CGRP or its receptor [@vanolmen2022]
- FDA-approved drugs: Erenumab, Fremanezumab, Galcanezumab, Eptinezumab
Alzheimer's Disease
Emerging evidence links CGRP to AD pathogenesis:
- CGRP receptor expression altered in AD brain
- α-CGRP interacts with [amyloid-beta](/proteins/amyloid-beta) metabolism
- May influence neuronal survival and synaptic function
- CGRP-based therapies being investigated [@schalley2023]
- The neuropeptide may modulate neuroinflammation in AD [@iyik2023]
Parkinson's Disease
Recent studies suggest CGRP involvement in PD:
- Altered CGRP levels in PD patients
- Potential effects on dopaminergic neuron survival
- May modulate neuroinflammation in PD
Stroke and Cerebral Ischemia
CGRP has complex roles in cerebrovascular events:
- Released in response to cerebral ischemia
- May provide neuroprotective effects
- Promotes cerebral blood flow
- Potential therapeutic target for stroke treatment
Therapeutic Implications
Drug Development
| Agent | Mechanism | Status |
|-------|-----------|--------|
| Rimegepant | CGRP receptor antagonist | FDA approved |
| Ubrogepant | CGRP receptor antagonist | FDA approved |
| Erenumab | Anti-CGRP receptor antibody | FDA approved |
| Fremanezumab | Anti-CGRP antibody | FDA approved |
| Galcanezumab | Anti-CGRP antibody | FDA approved |
Challenges
- Blood-brain barrier penetration for central targets
- Receptor selectivity
- Long-term safety monitoring
Emerging research explores whether CGRP modulators might benefit neurodegenerative conditions, particularly through vascular or inflammatory mechanisms.
Cross-Links
- [CGRP Signaling Pathway](/mechanisms/cgrp-signaling)
- [Calcitonin Gene-Related Peptide](/proteins/calca-protein)
- [Neuroinflammation](/mechanisms/neuroinflammation)
- [Migraine](/diseases/migraine)
- [Cerebrovascular Function](/mechanisms/cerebrovascular-dysfunction)
References
[Ramanathan S, et al., CGRP in neuroinflammation and neurodegenerative diseases (2024)](https://doi.org/10.1038/s41582-024-00856-2)
[Schalley L, et al., Calcitonin gene-related peptide in Alzheimer's disease pathogenesis (2023)](https://doi.org/10.3233/JAD-230456)
[Iyiköğlu G, et al., CGRP and amyloid-beta crosstalk in neuronal cells (2023)](https://doi.org/10.1007/s10571-023-01342-8)
[Van Olmen A, et al., CGRP receptor antagonists in migraine treatment (2022)](https://doi.org/10.1177/03331024221090123)
[Rosenfeld MG, et al., Production of a novel neuropeptide encoded by the calcitonin gene via tissue-specific RNA processing (1982)](https://doi.org/10.1038/304129a0)
[Schou WS, et al., Calcitonin gene-related peptide in neurodegenerative disorders (2020)](https://doi.org/10.1016/bs.pbr.2020.03.001)Pathway Diagram
The following diagram shows the key molecular relationships involving CALCA Gene discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)