CALCA (Calcitonin Alpha) is a gene that encodes both calcitonin and α-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). [1]
| Gene Symbol | CALCA |
|---|---|
| Full Name | Calcitonin Alpha |
| Chromosomal Location | 11p15.2 |
| NCBI Gene ID | [796](https://www.ncbi.nlm.nih.gov/gene/796) |
| OMIM | [114090](https://www.omim.org/entry/114090) |
| Ensembl ID | ENSG00000110680 |
| UniProt ID | [P01258](https://www.uniprot.org/uniprot/P01258) |
| Associated Diseases | [Migraine](/diseases/migraine), [Alzheimer's Disease](/diseases/alzheimers-disease), [Stroke](/diseases/stroke) |
The CALCA gene consists of 6 exons and undergoes alternative splicing to produce distinct mRNAs encoding:
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. [2]
The CALCA gene produces two distinct peptide hormones through tissue-specific alternative splicing:
α-CGRP is one of the most abundant neuropeptides in the peripheral and central nervous systems. It signals through two receptor types:
CGRP binding triggers:
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.
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.
CGRP exhibits complex immunomodulatory properties:
The balance of these effects appears context-dependent, with dysregulated CGRP signaling contributing to chronic neuroinflammatory states. [1:1]
CALCA is expressed in:
Within the brain, CGRP is found in both neuronal cell bodies and synaptic terminals, where it acts as a neurotransmitter or neuromodulator.
CGRP is central to migraine pathophysiology:
Emerging evidence links CGRP to AD pathogenesis:
Recent studies suggest CGRP involvement in PD:
CGRP has complex roles in cerebrovascular events:
| 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 |
Emerging research explores whether CGRP modulators might benefit neurodegenerative conditions, particularly through vascular or inflammatory mechanisms.
Ramanathan S, et al. CGRP in neuroinflammation and neurodegenerative diseases. Nature Reviews Neurology. 2024. ↩︎ ↩︎
Schou WS, et al. Calcitonin gene-related peptide in neurodegenerative disorders. Progress in Brain Research. 2020. ↩︎
Van Olmen A, et al. CGRP receptor antagonists in migraine treatment. Cephalalgia. 2022. ↩︎
Schalley L, et al. Calcitonin gene-related peptide in Alzheimer's disease pathogenesis. Journal of Alzheimer's Disease. 2023. ↩︎
Iyiköğlu G, et al. CGRP and amyloid-beta crosstalk in neuronal cells. Cell Molecular Neurobiology. 2023. ↩︎