Calcitonin gene-related peptide

From Wikipedia, the free encyclopedia

Calcitonin-related polypeptide alpha
Human calcitonin (black) bound to the calcitonin receptor. PDB: 7TYO​
Identifiers
Symbol	CALCA
Alt. symbols	CALC1
NCBI gene	796
HGNC	1437
OMIM	114130
RefSeq	NM_001741
UniProt	P06881
Other data
Locus	Chr. 11 p15.2
Search for Structures Swiss-model Domains InterPro

Calcitonin-related polypeptide, beta
Identifiers
Symbol	CALCB
Alt. symbols	CALC2
NCBI gene	797
HGNC	1438
OMIM	114160
RefSeq	NM_000728
UniProt	P10092
Other data
Locus	Chr. 11 p15.2
Search for Structures Swiss-model Domains InterPro

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). 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]

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.

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

[edit]

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]

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 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]

This section needs to be updated. Please help update this article to reflect recent events or newly available information. (February 2018)

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. 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]

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]

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. PMC 4187032. PMID 25287861.
2. ↑ Amara SG, Jonas V, Rosenfeld MG, Ong ES, Evans RM (July 1982). "Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products". Nature. 298 (5871): 240–4. Bibcode:1982Natur.298..240A. doi:10.1038/298240a0. PMID 6283379. S2CID 24188834.
3. ↑ Rezaeian AH, Isokane T, Nishibori M, Chiba M, Hiraiwa N, Yoshizawa M, Yasue H (October 2009). "alphaCGRP and betaCGRP transcript amount in mouse tissues of various developmental stages and their tissue expression sites". Brain & Development. 31 (9): 682–93. doi:10.1016/j.braindev.2008.10.011. PMID 19062206. S2CID 21635386.
4. ↑ Edvinsson L (May 2017). "The Trigeminovascular Pathway: Role of CGRP and CGRP Receptors in Migraine". Headache. 57 Suppl 2 (S2): 47–55. doi:10.1111/head.13081. PMID 28485848.
5. ↑ Rosenfeld MG, Mermod JJ, Amara SG, Swanson LW, Sawchenko PE, Rivier J, et al. (1983). "Production of a novel neuropeptide encoded by the calcitonin gene via tissue-specific RNA processing". Nature. 304 (5922): 129–35. Bibcode:1983Natur.304..129R. doi:10.1038/304129a0. PMID 6346105. S2CID 4322278.
6. ↑ Brain SD, Williams TJ, Tippins JR, Morris HR, MacIntyre I (1985). "Calcitonin gene-related peptide is a potent vasodilator". Nature. 313 (5997): 54–6. Bibcode:1985Natur.313...54B. doi:10.1038/313054a0. PMID 3917554. S2CID 4329128.
7. ↑ McCulloch J, Uddman R, Kingman TA, Edvinsson L (August 1986). "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. Bibcode:1986PNAS...83.5731M. doi:10.1073/pnas.83.15.5731. PMC 386363. PMID 3488550.
8. ↑ Chen LJ, Zhang FG, Li J, Song HX, Zhou LB, Yao BC, et al. (January 2010). "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. doi:10.1016/j.jocn.2009.03.042. PMID 19969463. S2CID 29249307.
9. 1 2 3 4 5 Norman A, Henry H, Litwack G (2014). Hormones. Amsterdam: Elsevier. 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 4107433. doi:10.1155/2022/4107433. ISSN 1942-0900. PMC 8817839. PMID 35132349.
11. 1 2 Gao X, Zhang D, Xu C, Li H, Caron KM, Frenette PS (January 2021). "Nociceptive nerves regulate haematopoietic stem cell mobilization". Nature. 589 (7843): 591–596. Bibcode:2021Natur.589..591G. doi:10.1038/s41586-020-03057-y. PMC 7856173. PMID 33361809.
12. ↑ Poyner DR, Sexton PM, Marshall I, Smith DM, Quirion R, Born W, et al. (June 2002). "International Union of Pharmacology. XXXII. The mammalian calcitonin gene-related peptides, adrenomedullin, amylin, and calcitonin receptors". Pharmacological Reviews. 54 (2): 233–46. doi:10.1124/pr.54.2.233. PMID 12037140. S2CID 17302944.
13. 1 2 3 Arulmani U, Maassenvandenbrink A, Villalón CM, Saxena PR (October 2004). "Calcitonin gene-related peptide and its role in migraine pathophysiology". European Journal of Pharmacology. 500 (1–3): 315–30. doi:10.1016/j.ejphar.2004.07.035. PMID 15464043.
14. ↑ Woolley MJ, Simms J, Mobarec JC, Reynolds CA, Poyner DR, Conner AC (October 2017). "Understanding the molecular functions of the second extracellular loop (ECL2) of the calcitonin gene-related peptide (CGRP) receptor using a comprehensive mutagenesis approach" (PDF). Molecular and Cellular Endocrinology. 454: 39–49. doi:10.1016/j.mce.2017.05.034. PMID 28572046. S2CID 13779528.
15. 1 2 Durham PL, Russo AF (February 2003). "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. doi:10.1523/JNEUROSCI.23-03-00807.2003. PMC 6741928. PMID 12574409.
16. ↑
17. ↑ Li J, Vause CV, Durham PL (February 2008). "Calcitonin gene-related peptide stimulation of nitric oxide synthesis and release from trigeminal ganglion glial cells". Brain Research. 1196: 22–32. doi:10.1016/j.brainres.2007.12.028. PMC 2268710. PMID 18221935.
18. ↑ Deen M, Correnti E, Kamm K, Kelderman T, Papetti L, Rubio-Beltrán E, et al. (September 2017). "Blocking CGRP in migraine patients - a review of pros and cons". The Journal of Headache and Pain. 18 (1) 96. doi:10.1186/s10194-017-0807-1. PMC 5612904. PMID 28948500.
19. ↑ Edvinsson L, Haanes KA, Warfvinge K, Krause DN (June 2018). "CGRP as the target of new migraine therapies - successful translation from bench to clinic". Nature Reviews. Neurology. 14 (6): 338–350. doi:10.1038/s41582-018-0003-1. PMID 29691490. S2CID 13810025.
20. ↑ Buzzi MG, Bonamini M, Moskowitz MA (1995). "Neurogenic model of migraine". Cephalalgia. 15 (4): 277–80. doi:10.1046/j.1468-2982.1995.1504277.x. PMID 7585923. S2CID 1403941.
21. ↑ Goto K, Miyauchi T, Homma S, Ohshima N (June 1992). "Calcitonin gene-related peptide in the regulation of cardiac function". Annals of the New York Academy of Sciences. 657 (1): 194–203. Bibcode:1992NYASA.657..194G. doi:10.1111/j.1749-6632.1992.tb22768.x. PMID 1637085. S2CID 43409084.
22. ↑ Joyce CD, Fiscus RR, Wang X, Dries DJ, Morris RC, Prinz RA (December 1990). "Calcitonin gene-related peptide levels are elevated in patients with sepsis". Surgery. 108 (6): 1097–101. PMID 2247835.
23. ↑ Edvinsson L, Goadsby PJ (October 1994). "Neuropeptides in migraine and cluster headache". Cephalalgia. 14 (5): 320–7. doi:10.1046/j.1468-2982.1994.1405320.x. PMID 7828188. S2CID 29949980.
24. ↑ Ferrari MD, Saxena PR (June 1993). "On serotonin and migraine: a clinical and pharmacological review". Cephalalgia. 13 (3): 151–65. doi:10.1046/j.1468-2982.1993.1303151.x. PMID 8395342. S2CID 23099581.
25. ↑ Goadsby PJ, Edvinsson L (June 1994). "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. doi:10.1093/brain/117.3.427. PMID 7518321.
26. 1 2 3 4 Tepper S. "What to Know About the New CGRP Migraine Treatment Options". American Migraine Foundation. Retrieved 23 February 2019.
27. ↑ Pellesi L, Guerzoni S, Pini LA (November 2017). "Spotlight on Anti-CGRP Monoclonal Antibodies in Migraine: The Clinical Evidence to Date". Clinical Pharmacology in Drug Development. 6 (6): 534–547. doi:10.1002/cpdd.345. PMC 5697612. PMID 28409893.
28. 1 2 3 Durham PL (June 2006). "Calcitonin gene-related peptide (CGRP) and migraine". Headache. 46 (Suppl 1): S3-8. doi:10.1111/j.1526-4610.2006.00483.x. PMC 3134175. PMID 16927957.
29. 1 2 Goadsby PJ, Edvinsson L, Ekman R (August 1990). "Vasoactive peptide release in the extracerebral circulation of humans during migraine headache". Annals of Neurology. 28 (2): 183–7. doi:10.1002/ana.410280213. PMID 1699472. S2CID 12568270.
30. 1 2 Edvinsson L (2006). "Neuronal signal substances as biomarkers of migraine". Headache. 46 (7): 1088–94. doi:10.1111/j.1526-4610.2006.00502.x. PMID 16866713. S2CID 24433430.
31. ↑ Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B, Olesen J (February 2002). "CGRP may play a causative role in migraine". Cephalalgia. 22 (1): 54–61. doi:10.1046/j.1468-2982.2002.00310.x. PMID 11993614. S2CID 24779840.
32. ↑ Wang W, Wang EQ, Balthasar JP (November 2008). "Monoclonal antibody pharmacokinetics and pharmacodynamics". Clinical Pharmacology and Therapeutics. 84 (5): 548–58. doi:10.1038/clpt.2008.170. PMID 18784655. S2CID 7994962.
33. ↑ Rosenberg J (18 May 2018). "FDA Approves Erenumab, First CGRP Inhibitor for Prevention of Migraine". AJMC.com. Retrieved 23 February 2019.
34. ↑ Lattanzi S, Brigo F, Trinka E, Vernieri F, Corradetti T, Dobran M, Silvestrini M (March 2019). "Erenumab for Preventive Treatment of Migraine: A Systematic Review and Meta-Analysis of Efficacy and Safety". Drugs. 79 (4): 417–431. doi:10.1007/s40265-019-01069-1. PMID 30793254. S2CID 67790108.
35. ↑ "FDA Approves Second Anti-CGRP Treatment for Migraines". American Migraine Foundation. Retrieved 23 February 2019.
36. ↑ Bigal ME, Rapoport AM, Silberstein SD, Walter S, Hargreaves RJ, Aycardi E (November 2018). "From LBR-101 to Fremanezumab for Migraine". CNS Drugs. 32 (11): 1025–1037. doi:10.1007/s40263-018-0579-4. PMID 30311143. S2CID 52962394.
37. ↑ "Lilly's Emgality™ (galcanezumab-gnlm) Receives U.S. FDA Approval for the Preventive Treatment of Migraine in Adults". Lilly. Retrieved 23 February 2019.
38. ↑ Lamb YN (November 2018). "Galcanezumab: First Global Approval". Drugs. 78 (16): 1769–1775. doi:10.1007/s40265-018-1002-7. PMID 30378008. S2CID 53107438.
39. ↑ "Nurtec (Rimegepant) becomes first migraine therapy for acute and preventive treatment". CGRP Forum. 2025-07-09. Retrieved 2025-07-09.
40. ↑ "FDA Approves Qulipta (atogepant) Oral CGRP Receptor Antagonist for the Preventive Treatment of Migraine". Drugs.com. Retrieved 19 September 2024.
41. ↑ "Degradants Formed During Phytocannabinoid Processing". www.caymanchem.com. Retrieved 2023-05-10.
42. ↑ Zygmunt PM, Andersson DA, Hogestatt ED (June 2002). "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. doi:10.1523/JNEUROSCI.22-11-04720.2002. PMC 6758782. PMID 12040079.

• Calcitonin+Gene-Related+Peptide at the U.S. National Library of Medicine Medical Subject Headings (MeSH)