Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide found in the nervous system. It is a potent vasodilator and a modulator of cerebrovascular pain. CGRP exists in two main in vivo forms: αCGRP and βCGRP. αCGRP is primarily encoded by the calcitonin gene (also known as the CALCA gene). It is synthesized post-transcriptionally through specific splicing, resulting in two different products of αCGRP and CT. βCGRP is encoded by the CALCB gene. These two peptides play a central role in pain perception, vasomotor regulation, and inflammatory responses, and are targets for the treatment of primary headache disorders such as migraines. Blocking CGRP or its receptors using CGRP-targeting drugs can help alleviate migraine symptoms.
CGRP expression distribution and function
The 37 amino acids that make up CGRP and its two isoforms (CALCA and CALCB) are mainly expressed in neurons of the central and peripheral nervous systems. CALCA is also expressed in ductal cells, pancreatic islet cells, and parietal cells; CALCB is also expressed in ductal cells, barrier epithelial cells, acinar cells, and nephron cells.
(Data source: unprot)
CGRP is secreted by sensory nerve cells and has multiple effects on bone tissue. CGRP can bind to CLR receptors on the cell surface, directly enhancing osteoblasts and the expression of osteogenic genes. CGRP can inhibit the RANKL/RANK/NF-κB pathway by increasing OPG levels, thereby inhibiting osteoclast proliferation and reducing osteoclast activity. CGRP can promote the expression of VEGF and HIF factors, enhance angiogenesis in vascular endothelial cells, induce angiogenesis, and provide nutritional support for bone repair. CGRP can enhance the transformation of M0 macrophages into M2 macrophages and regulate the immune microenvironment for bone repair.
(Data source: Eller MT, et al. Int J Mol Sci. 2024)
The structure of CGRP and its receptor
CAL CA and CAL C B are secreted proteins, composed of a signal peptide, an N-terminal peptide, a mature active peptide, and a C-terminal peptide. Later, through signal peptide cleavage, enzymatic cleavage, and C-terminal amidation, they form a mature peptide chain.
CAL CA and CAL C B have similar mature peptide chain structures. Both are polypeptides composed of 37 amino acids, with an N-terminal disulfide ring (formed by cysteine residues at positions 2 and 7, crucial for maintaining structural stability and binding to the receptor) and a C-terminal amidation modification (essential for biological activity). The CGRP receptor is a heterodimeric complex composed of a calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1).
(Data source: Alphafold)
CGRP signaling pathways and regulation
CGRP transmits signals to cells via the G protein-coupled receptor-CLR-RAMP1 dimer, mainly including the cAMP signaling pathway and the phosphatidylinositol signaling pathway.
cAMP signaling pathway: activates G proteins and AC to increase intracellular second messengers. cAMP concentration activates PKA and CREB and promotes mRNA transcription in the cell nucleus.
Phosphatidylinositol signaling pathway: By activating PLCβ1, PIP2 is hydrolyzed to generate the second messengers IP3 and DAG. IP3 binds to its ligand on the endoplasmic reticulum, thereby opening endoplasmic reticulum channels. Calcium channel binding increases intracellular Ca2 + concentration and activates various calcium-dependent proteins. DAG attaches to the cell membrane, activating membrane-bound PKC. Furthermore, free intracellular PKC can phosphorylate serine/threonine residues in proteins, producing biological effects.
(Data source: Wang Q, et al. Biomolecules. 2023)
Targeted therapy for CGRP
CGRP has now become the focus of numerous studies, which have shown that monoclonal antibodies have a significant effect on the prevention and cessation of migraine attacks. Currently, four monoclonal antibodies (Erenumab, Galcanezumab, Fremanezumab, and Eptinezumab) are available on the market and have been approved for the treatment of paroxysmal and chronic migraines.
Galcanezumab, developed by Eli Lilly, was first approved by the FDA in September 2018 for the preventative treatment of migraines in adults. In June 2019, it received FDA approval for a new indication: the treatment of episodic cluster headache (ECH) in adults.
(Data source: Eller MT, et al. Int J Mol Sci. 2024)
