Biology:Calcitonin gene-related peptide

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Calcitonin-related polypeptide alpha
Human calcitonin (black) bound to the calcitonin receptor. PDB: 7TYO​
Identifiers
SymbolCALCA
Alt. symbolsCALC1
NCBI gene796
HGNC1437
OMIM114130
RefSeqNM_001741
UniProtP06881
Other data
LocusChr. 11 p15.2{{{LocusSupplementaryData}}}
Calcitonin-related polypeptide, beta
Identifiers
SymbolCALCB
Alt. symbolsCALC2
NCBI gene797
HGNC1438
OMIM114160
RefSeqNM_000728
UniProtP10092
Other data
LocusChr. 11 p15.2{{{LocusSupplementaryData}}}

Calcitonin gene-related peptide (CGRP) is a neuropeptide that belongs to the calcitonin family.[1] Human CGRP consists of two isoforms, CGRP alpha (α-CGRP, also known as CGRP I) and CGRP beta (β-CGRP, also known as CGRP II).[2] α-CGRP is a 37-amino acid neuropeptide formed by alternative splicing[3] of the calcitonin/CGRP gene located on chromosome 11. β-CGRP is less studied. In humans, β-CGRP differs from α-CGRP by three amino acids and is encoded in a separate, nearby gene.[4] The CGRP family includes calcitonin (CT), adrenomedullin (AM), and amylin (AMY).[5]

Function

CGRP is produced in both peripheral and central neurons.[6] It is a potent peptide vasodilator and can function in the transmission of nociception.[7][8] In the spinal cord, the function and expression of CGRP may differ depending on the location of synthesis. CGRP is derived mainly from the cell bodies of motor neurons when synthesized in the ventral horn of the spinal cord and may contribute to the regeneration of nervous tissue after injury. Conversely, CGRP is derived from dorsal root ganglion when synthesized in the dorsal horn of the spinal cord and may be linked to the transmission of pain.[9] In the trigeminal vascular system, the cell bodies of the trigeminal ganglion are the main source of CGRP. CGRP is thought to play a role in cardiovascular homeostasis and nociception. In the heart, CGRP acts as a chronotrope by increasing heart rate.[10]: 202  Apart from these attributes, CGRP is known to modulate the autonomic nervous system and plays a role in ingestion.[10]: 201–204 

CGRP has moderate effects on calcium homeostasis compared to its extensive actions in other areas, such as the autonomic nervous system.

Functions

As a neuropeptide, CGRP acts as an appetite suppressant and contributes to gastric acid secretion.[10] It also functions in temperature homeostasis, increases heart rate, and plays a role in the release of the pituitary hormones in a paracrine manner.[10] Because of these characteristics, it has been said that CGRP functions more as a neurotransmitter than a hormone.[10]

Stem cell mobilization

CGRP has a role in human stem cell (HSC) mobilization.[11] In investigations carried out in 2021, treatment with CGRP resulted in significantly increased CGRP levels in the bone marrow extracellular fluid and substantially increased the number of HSCs mobilized by granulocyte colony-stimulating factor (G-CSF).[12] The authors of the 2021 study concluded that G-CSF-induced HSC mobilization is regulated by the nociceptor nerve-derived neuropeptide CGRP. This peptide exerts its effect on HSC mobilization via the receptor activity-modifying protein 1 (RAMP1) pathway.[12]

Receptors

Structure of the human calcitonin receptor-Gs complex. The calcitonin transmembrane receptor (blue) is bound to human calcitonin (red) and the Gs complex (yellow). PDB: 7TYO​

CGRP mediates its effects through a heteromeric receptor composed of a G protein-coupled receptor called calcitonin receptor-like receptor (CALCRL) and RAMP1.[13] CGRP receptors are found throughout all the body, suggesting that the protein may modulate a variety of physiological functions in all major systems (e.g., respiratory, endocrine, gastrointestinal, immune, and cardiovascular).[14] These transmembrane receptors form folded accordion-like structures embedded in the cell membrane with loops of protein on the inside (intracellular loops) and outside (extracellular loops) of the membrane. The second extracellular loop is fundamental for ligand-induced activation, with key interactions of R274/Y278/D280/W283.[15]

Regulation

Regulation of the CGRP gene is in part controlled by the expression of the mitogen-activated protein kinase (MAPK) signaling pathway and cytokines like TNFα and iNOS.[16][17][18] 5HT1 receptor agonists like sumatriptan increase intracellular calcium, which causes decreases in CGRP promoter activity.[16]

CGRP receptors are found in myelinated A-fiber axons which is required for ligand specificity and function of the receptor. The CGRP receptor has three subunits: receptor activity-modifying protein 1 (RAMP1), calcitonin-like receptor (CLR) and receptor component protein (RCP).[19] The complex central receptor is the G protein-coupled receptor calcitonin receptor-like receptor (CALCRL) which is necessary for CGRP and adrenomedullin (AM receptors). For function CGRP, CALCRL must coincide with RAMP1 where the ligand-binding domain of CGRP is located. It also includes two cytoplasmic proteins that associate with the CALCRL-RAMP1 to form signal transduction. CALCRL contains the Gα subunit, which activates adenylyl cyclase and cAMP-dependent signaling pathways. Receptor-mediated transduction elevates in intracellular cAMP activate protein kinase A, which results in the phosphorylation of multiple targets, including potassium- sensitive ATP channels (KATP channels), extracellular signal-related kinases and transcription factors such as cAMP-responsive element-binding protein (CREB). In smooth muscle of neurovascular region, the elevation of cAMP upon CGRP activation results in vasodilation of the blood vessel. Chronic exposure to CGRP causes degradation of lysosomes.[20]

Research

Increased levels of CGRP have been reported in migraine and temporomandibular joint disorder patients as well as a variety of other diseases such as cardiac failure, hypertension, and sepsis.[21][22][23][24][25][26][27]

There is mounting evidence to suggest that CGRP may be beneficial in preventing the development of hypertension and cardiovascular pathologies associated with hypertension.[2] This is of particular concern, as females (16.6%) are more genetically predisposed to migraine than are males (7.5%).[28]

Preclinical evidence suggests that, during a migraine, activated primary sensory neurons (meningeal nociceptors) in the trigeminal ganglion release CGRP from their peripherally projecting nerve endings located within the meninges.[29][27] This CGRP then binds to and activates CGRP receptors located around meningeal vessels, causing vasodilation, mast cell degranulation, and plasma extravasation.[14][29][30][31] Human observations have further implicated the role of CGRP in the pathophysiology of migraine. Activation of primary sensory neurons in the trigeminal vascular system in humans can cause the release of CGRP. During some migraine attacks, increased concentrations of CGRP can be found in both saliva and in plasma drawn from the external jugular vein.[14][29][30][31] Furthermore, intravenous administration of alpha-CGRP is able to induce headache in individuals susceptible to migraine.[32][27]

Medicines

Treatments based on monoclonal antibodies have been produced related to CGRP or CGRP receptors. They have been shown to be effective in patients who experience migraine headaches, both with and without aura, and both episodic and chronic cluster headache. These are the first class of preventive medications originally designed and approved for people with migraine.[27] While these medications are often considered to have no or few side effects, a growing number of patients have reported severe, ongoing side effects including disabling lower back pain, muscle pain, neuropathy, and more. Due to the nature of the monoclonal antibodies, they must be administered parenterally, preferably by injection.[33]

The first CGRP related medication approved by the FDA is called erenumab (trade name Aimovig), produced by pharmaceutical company Amgen and Novartis. It interacts with the CGRP receptor. It is injected once monthly with a dose of 70 or 140 mg. Few adverse effects were reported (most related to injection site reactions) and patients had a significant reduction in migraines.[34][35]

The second approved by the FDA is called fremanezumab (trade name Ajovy), produced by the Teva Pharmaceuticals company. It interacts with the CGRP protein, whose expression is related to migraine attacks. It may be administered monthly or every three months, giving options for users. Trials have shown a reduction of greater than 50% of migraine days for those who responded. There were few significant side effects during trials, most related to injection site reactions.[36][37]

The third approved by the FDA is called galcanezumab (trade name Emgality), produced by the Eli Lilly and Company. It interacts with the CGRP protein, whose expression is related to migraine attacks. It is injected once a month, after the first month having a double dose. The main reported side effects are injection site reactions, although there are a growing number of reports of severe side effects from a minority of patients.[38][39]

Approved by the FDA in February 2020, ubrogepant (Ubrelvy) is an oral medication manufactured by AbbVie.

Also FDA approved in February 2020, eptinezumab (Vyepti), is an intravenous migraine prophylactic medication manufactured by Lundbeck.

Rimegepant (Nurtec ODT) subsequently became the first oral CGRP receptor antagonist to be approved by the FDA for both acute migraine treatment (approved February 2020) and prevention of episodic migraine (approved June 2021).[40] It is manufactured by Pfizer.

In September 2021 the FDA approved Qulipta (atogepant), the first oral CGRP receptor antagonist approved to prevent chronic migraine.[41]

The phytocannabinoids delta-9 tetrahydrocannabinol (Δ9-THC) and its oxidative byproduct cannabinol (CBN) are found to induce a CB1 and CB2 cannabinoid receptor-independent release of calcitonin gene-related peptide from capsaicin-sensitive perivascular sensory nerves, an action that other psychotropic cannabinoids cannot do.[42][43]

References

  1. ↑ Russell, F. A.; King, R.; Smillie, S.-J.; Kodji, X.; Brain, S. D. (October 2014). "Calcitonin Gene-Related Peptide: Physiology and Pathophysiology". Physiological Reviews 94 (4): 1099–1142. doi:10.1152/physrev.00034.2013. ISSN 0031-9333. PMID 25287861. 
  2. ↑ "Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products". Nature 298 (5871): 240–4. July 1982. doi:10.1038/298240a0. PMID 6283379. Bibcode: 1982Natur.298..240A. 
  3. ↑ "alphaCGRP and betaCGRP transcript amount in mouse tissues of various developmental stages and their tissue expression sites". Brain & Development 31 (9): 682–93. October 2009. doi:10.1016/j.braindev.2008.10.011. PMID 19062206. 
  4. ↑ "The Trigeminovascular Pathway: Role of CGRP and CGRP Receptors in Migraine". Headache 57 Suppl 2 (S2): 47–55. May 2017. doi:10.1111/head.13081. PMID 28485848. 
  5. ↑ "Production of a novel neuropeptide encoded by the calcitonin gene via tissue-specific RNA processing". Nature 304 (5922): 129–35. 1983. doi:10.1038/304129a0. PMID 6346105. Bibcode: 1983Natur.304..129R. 
  6. ↑ "Calcitonin gene-related peptide is a potent vasodilator". Nature 313 (5997): 54–6. 1985. doi:10.1038/313054a0. PMID 3917554. Bibcode: 1985Natur.313...54B. 
  7. ↑ "Calcitonin gene-related peptide: functional role in cerebrovascular regulation". Proceedings of the National Academy of Sciences of the United States of America 83 (15): 5731–5. August 1986. doi:10.1073/pnas.83.15.5731. PMID 3488550. Bibcode: 1986PNAS...83.5731M. 
  8. ↑ "Expression of calcitonin gene-related peptide in anterior and posterior horns of the spinal cord after brachial plexus injury". Journal of Clinical Neuroscience 17 (1): 87–91. January 2010. doi:10.1016/j.jocn.2009.03.042. PMID 19969463. 
  9. ↑ 10.0 10.1 10.2 10.3 10.4 Hormones. Amsterdam: Elsevier. 2014. ISBN 978-0-12-369444-7. 
  10. ↑ Lv, Xiaoting; Chen, Qingquan; Zhang, Shuyu; Gao, Feng; Liu, Qicai (2022-01-29). "CGRP: A New Endogenous Cell Stemness Maintenance Molecule". Oxidative Medicine and Cellular Longevity 2022. doi:10.1155/2022/4107433. ISSN 1942-0900. PMID 35132349. 
  11. ↑ 12.0 12.1 "Nociceptive nerves regulate haematopoietic stem cell mobilization". Nature 589 (7843): 591–596. January 2021. doi:10.1038/s41586-020-03057-y. PMID 33361809. Bibcode: 2021Natur.589..591G. 
  12. ↑ "International Union of Pharmacology. XXXII. The mammalian calcitonin gene-related peptides, adrenomedullin, amylin, and calcitonin receptors". Pharmacological Reviews 54 (2): 233–46. June 2002. doi:10.1124/pr.54.2.233. PMID 12037140. 
  13. ↑ 14.0 14.1 14.2 "Calcitonin gene-related peptide and its role in migraine pathophysiology". European Journal of Pharmacology 500 (1–3): 315–30. October 2004. doi:10.1016/j.ejphar.2004.07.035. PMID 15464043. 
  14. ↑ "Understanding the molecular functions of the second extracellular loop (ECL2) of the calcitonin gene-related peptide (CGRP) receptor using a comprehensive mutagenesis approach". Molecular and Cellular Endocrinology 454: 39–49. October 2017. doi:10.1016/j.mce.2017.05.034. PMID 28572046. http://repository.essex.ac.uk/19762/1/Molecular_functions_of_ECL2_of_CGRP.pdf. 
  15. ↑ 16.0 16.1 "Stimulation of the calcitonin gene-related peptide enhancer by mitogen-activated protein kinases and repression by an antimigraine drug in trigeminal ganglia neurons". The Journal of Neuroscience 23 (3): 807–15. February 2003. doi:10.1523/JNEUROSCI.23-03-00807.2003. PMID 12574409. 
  16. ↑ "Tumor necrosis factor-alpha induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons". The Journal of Neuroscience 23 (7): 2517–21. April 2003. doi:10.1523/JNEUROSCI.23-07-02517.2003. PMID 12684435. 
  17. ↑ "Calcitonin gene-related peptide stimulation of nitric oxide synthesis and release from trigeminal ganglion glial cells". Brain Research 1196: 22–32. February 2008. doi:10.1016/j.brainres.2007.12.028. PMID 18221935. 
  18. ↑ "Blocking CGRP in migraine patients - a review of pros and cons". The Journal of Headache and Pain 18 (1). September 2017. doi:10.1186/s10194-017-0807-1. PMID 28948500. 
  19. ↑ "CGRP as the target of new migraine therapies - successful translation from bench to clinic". Nature Reviews. Neurology 14 (6): 338–350. June 2018. doi:10.1038/s41582-018-0003-1. PMID 29691490. 
  20. ↑ "Neurogenic model of migraine". Cephalalgia 15 (4): 277–80. 1995. doi:10.1046/j.1468-2982.1995.1504277.x. PMID 7585923. 
  21. ↑ "Calcitonin gene-related peptide in the regulation of cardiac function". Annals of the New York Academy of Sciences 657 (1): 194–203. June 1992. doi:10.1111/j.1749-6632.1992.tb22768.x. PMID 1637085. Bibcode: 1992NYASA.657..194G. 
  22. ↑ "Calcitonin gene-related peptide levels are elevated in patients with sepsis". Surgery 108 (6): 1097–101. December 1990. PMID 2247835. 
  23. ↑ "Neuropeptides in migraine and cluster headache". Cephalalgia 14 (5): 320–7. October 1994. doi:10.1046/j.1468-2982.1994.1405320.x. PMID 7828188. 
  24. ↑ "On serotonin and migraine: a clinical and pharmacological review". Cephalalgia 13 (3): 151–65. June 1993. doi:10.1046/j.1468-2982.1993.1303151.x. PMID 8395342. 
  25. ↑ "Human in vivo evidence for trigeminovascular activation in cluster headache. Neuropeptide changes and effects of acute attacks therapies". Brain 117 ( Pt 3) (3): 427–34. June 1994. doi:10.1093/brain/117.3.427. PMID 7518321. 
  26. ↑ 27.0 27.1 27.2 27.3 "What to Know About the New CGRP Migraine Treatment Options". https://americanmigrainefoundation.org/resource-library/what-to-know-about-the-new-anti-cgrp-migraine-treatment-options/. 
  27. ↑ "Spotlight on Anti-CGRP Monoclonal Antibodies in Migraine: The Clinical Evidence to Date". Clinical Pharmacology in Drug Development 6 (6): 534–547. November 2017. doi:10.1002/cpdd.345. PMID 28409893. 
  28. ↑ 29.0 29.1 29.2 "Calcitonin gene-related peptide (CGRP) and migraine". Headache 46 (Suppl 1): S3-8. June 2006. doi:10.1111/j.1526-4610.2006.00483.x. PMID 16927957. 
  29. ↑ 30.0 30.1 "Vasoactive peptide release in the extracerebral circulation of humans during migraine headache". Annals of Neurology 28 (2): 183–7. August 1990. doi:10.1002/ana.410280213. PMID 1699472. 
  30. ↑ 31.0 31.1 "Neuronal signal substances as biomarkers of migraine". Headache 46 (7): 1088–94. 2006. doi:10.1111/j.1526-4610.2006.00502.x. PMID 16866713. 
  31. ↑ "CGRP may play a causative role in migraine". Cephalalgia 22 (1): 54–61. February 2002. doi:10.1046/j.1468-2982.2002.00310.x. PMID 11993614. 
  32. ↑ "Monoclonal antibody pharmacokinetics and pharmacodynamics". Clinical Pharmacology and Therapeutics 84 (5): 548–58. November 2008. doi:10.1038/clpt.2008.170. PMID 18784655. 
  33. ↑ "FDA Approves Erenumab, First CGRP Inhibitor for Prevention of Migraine". 18 May 2018. https://www.ajmc.com/newsroom/fda-approves-erenumab-first-cgrp-inhibitor-for-prevention-of-migraine. 
  34. ↑ "Erenumab for Preventive Treatment of Migraine: A Systematic Review and Meta-Analysis of Efficacy and Safety". Drugs 79 (4): 417–431. March 2019. doi:10.1007/s40265-019-01069-1. PMID 30793254. 
  35. ↑ "FDA Approves Second Anti-CGRP Treatment for Migraines". https://americanmigrainefoundation.org/resource-library/fda-approves-second-anti-cgrp-treatment-for-migraine/. 
  36. ↑ "From LBR-101 to Fremanezumab for Migraine". CNS Drugs 32 (11): 1025–1037. November 2018. doi:10.1007/s40263-018-0579-4. PMID 30311143. 
  37. ↑ "Lilly's Emgality™ (galcanezumab-gnlm) Receives U.S. FDA Approval for the Preventive Treatment of Migraine in Adults". https://investor.lilly.com/news-releases/news-release-details/lillys-emgalitytm-galcanezumab-gnlm-receives-us-fda-approval. 
  38. ↑ "Galcanezumab: First Global Approval". Drugs 78 (16): 1769–1775. November 2018. doi:10.1007/s40265-018-1002-7. PMID 30378008. 
  39. ↑ "Nurtec (Rimegepant) becomes first migraine therapy for acute and preventive treatment". 2025-07-09. https://www.cgrpforum.org/nurtec-rimegepant-becomes-first-migraine-therapy-for-acute-and-preventive-treatment/. 
  40. ↑ "FDA Approves Qulipta (atogepant) Oral CGRP Receptor Antagonist for the Preventive Treatment of Migraine". https://www.drugs.com/newdrugs/fda-approves-qulipta-atogepant-oral-cgrp-receptor-antagonist-preventive-migraine-5674.html. 
  41. ↑ "Degradants Formed During Phytocannabinoid Processing" (in en). https://www.caymanchem.com/news/degradants-formed-during-phytocannabinoid-processing. 
  42. ↑ "Δ9-Tetrahydrocannabinol and Cannabinol Activate Capsaicin-Sensitive Sensory Nerves via a CB1 and CB2 Cannabinoid Receptor-Independent Mechanism". The Journal of Neuroscience 22 (11): 4720–7. June 2002. doi:10.1523/JNEUROSCI.22-11-04720.2002. PMID 12040079. 



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