CALCA

Official Full Name

calcitonin related polypeptide alpha

Organism

Homo sapiens

GeneID

796

Background

This gene encodes the peptide hormones calcitonin, calcitonin gene-related peptide and katacalcin by tissue-specific alternative RNA splicing of the gene transcripts and cleavage of inactive precursor proteins. Calcitonin is involved in calcium regulation and acts to regulate phosphorus metabolism. Calcitonin gene-related peptide functions as a vasodilator and as an antimicrobial peptide while katacalcin is a calcium-lowering peptide. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Aug 2014]

Synonyms

CT; KC; PCT; CGRP; CALC1; CGRP1; CGRP-I; CGRP-alpha;

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Detailed Information

The CALCA gene, located on human chromosome 11p15.2, exemplifies the complexity and precision of eukaryotic gene expression. Through tissue-specific alternative RNA splicing, a single transcript gives rise to two distinct biologically active peptides: calcitonin (CT) and calcitonin gene-related peptide (CGRP). Additionally, post-translational proteolytic processing of the precursor protein can generate a third active peptide, katacalcin. This "one gene, multiple products" mechanism allows CALCA to perform divergent physiological roles depending on the tissue context.

In thyroid parafollicular cells, the primary transcript encodes the calcitonin precursor, which is processed into mature calcitonin. In contrast, in the nervous and cardiovascular systems, selective splicing skips the calcitonin exon, yielding CGRP, which exists in two major isoforms: α-CGRP, encoded by CALCA, and β-CGRP, encoded by the homologous CALCB gene. These isoforms have overlapping but subtly distinct functions, forming a finely tuned regulatory network. Such complex transcriptional and post-translational regulation ensures that CALCA products exert precise effects at the right time and place, underpinning their multifunctional biological roles.

Biological Significance

CALCA gene products are involved in calcium-phosphate homeostasis, neuro-immune-vascular communication, and more. Calcitonin primarily inhibits osteoclast-mediated bone resorption, promoting calcium and phosphate deposition in bone. This acute hypocalcemic effect counterbalances parathyroid hormone, maintaining mineral metabolism.

CGRP is recognized as one of the most potent endogenous vasodilators. By binding its specific receptor, CGRP induces relaxation of coronary, cerebral, and peripheral vessels, regulating local blood flow, blood pressure, and microcirculation. In the central and peripheral nervous systems, CGRP functions as a neurotransmitter and neuromodulator, modulating pain signaling, initiating and sustaining inflammation, and regulating autonomic functions.

Figure 1. Schematic representation of a CGRP receptor. (Iyengar S, et al., 2017)

Notably, CGRP released from sensory nerve terminals triggers neurogenic inflammation, causing vasodilation, plasma protein extravasation, and mast cell degranulation-critical mechanisms in pain and inflammatory disorders. CGRP also exhibits direct antimicrobial activity, suggesting a role in innate immune defense and forming a communication link between the nervous and immune systems. Katacalcin primarily contributes to calcium homeostasis, with mechanisms and physiological significance still under investigation. Together, CALCA products serve as multifunctional regulators in bone metabolism, cardiovascular homeostasis, neural signaling, immune defense, and inflammation, with dysregulation implicated in various diseases.

Clinical Relevance

The clinical importance of CALCA, particularly CGRP, is most prominent in migraine pathophysiology and treatment. During migraine attacks, abnormal activation of the trigeminovascular system leads to massive CGRP release from sensory nerve endings, causing severe intracranial vasodilation and neurogenic inflammation, producing throbbing headache and associated symptoms. This discovery established CGRP and its receptor as revolutionary therapeutic targets.

Clinically approved therapies include: CGRP receptor antagonists and monoclonal antibodies targeting CGRP or its receptor, which effectively and specifically block CGRP signaling, providing excellent efficacy and safety in prevention and treatment of migraine, transforming the clinical management of this condition.

Beyond migraine, CGRP plays important roles in cardiovascular physiology. In shock states, compensatory CGRP release may help maintain perfusion of vital organs, while excessive vasodilation may contribute to hypotension. In chronic conditions like atherosclerosis, hypertension, and heart failure, CGRP signaling may be disrupted, and loss of its protective function can exacerbate disease progression, making CGRP modulation a potential therapeutic avenue.

In oncology, aberrant CALCA expression and methylation patterns may serve as cancer biomarkers. Additionally, calcitonin analogs have long been used to inhibit bone resorption in osteoporosis and Paget's disease. However, systemic long-term CGRP blockade requires caution due to potential impacts on cardiovascular protection, immune surveillance, and bone metabolism. Future research aims to clarify the precise roles of CALCA-derived peptides in specific disease microenvironments and develop tissue-targeted modulation strategies.

References

Russell FA, King R, Smillie SJ, Kodji X, Brain SD. Calcitonin gene-related peptide: physiology and pathophysiology. Physiol Rev. 2014;94(4):1099–1142.
Iyengar S, Ossipov MH, Johnson KW. The role of calcitonin gene-related peptide in peripheral and central pain mechanisms including migraine. Pain. 2017;158(4):543–559.

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