Calcitonin gene-related peptide

Calcitonin gene-related peptide (CGRP) is a member of the calcitonin family of peptides consisting of calcitonin, amylin, adrenomedullin, adrenomedullin 2 (intermedin) and calcitonin‑receptor‑stimulating peptide. Calcitonin is mainly produced by thyroid C cells whilst CGRP is secreted and stored in the nervous system.[1] This peptide, in humans, exists in two forms: CGRP alpha (α-CGRP or CGRP I), and CGRP beta (β-CGRP or CGRP II).[2] α-CGRP is a 37-amino acid neuropeptide and is 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]

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
Search for
StructuresSwiss-model
DomainsInterPro
Calcitonin-related polypeptide, beta
Identifiers
SymbolCALCB
Alt. symbolsCALC2
NCBI gene797
HGNC1438
OMIM114160
RefSeqNM_000728
UniProtP10092
Other data
LocusChr. 11 p14.2-p12
Search for
StructuresSwiss-model
DomainsInterPro

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 on 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.

Appetite

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 cells mobilization. In investigations carried out during last five years, treatment with CGRP resulted in significantly increased CGRP levels in the bone marrow extracellular fluid and substantially increased the number of HSCs mobilized by G-CSF.[11] The results performed on different experiments by the same research group led to the conclusion that G-CSF-induced HSC mobilization is regulated by the nociceptor nerve-derived neuropeptide CGRP. This peptide exerts its effect on HSC mobilization by Ramp 1 pathway.[11]

Receptors
Structure of the human calcitonin recptor-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 a receptor activity-modifying protein (RAMP1).[12] 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).[13] The extracellular loop number 2 is fundamental for ligand induced activation, with key interactions of R274/Y278/D280/W283.[14]

Regulation

Regulation of the calcitonin gene-related peptide (CGRP) gene is in part controlled by the expression of the mitogen-activated protein kinases (MAPK) signaling pathway,[15] cytokines such as TNFα[16] and iNOS.[17]

5HT1 receptor agonists, such as sumatriptan, increase intracellular calcium, which cause decreases in CGRP promoter activity.[15]

CGRP receptor is found in myelinated A-fibers axon 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).[18] 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.[19]

Research
Further information: Calcitonin gene-related peptide receptor antagonist

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.[20][21][22][23][24][25][26]

There is mounting evidence to suggest that CGRP may be beneficial in preventing the development of hypertension and cardiovascular pathologies associated with hypertension.[2] Prophylactic therapy with calcitonin gene‐related peptides (CGRPs) may have unknown fertility consequences for women of child bearing age. This is of particular concern, as females (16.6%) are more genetically predisposed to migraine than are males (7.5%).[27]

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.[28][26] This CGRP then binds to and activates CGRP receptors located around meningeal vessels, causing vasodilation, mast cell degranulation, and plasma extravasation.[13][28][29][30] 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.[13][28][29][30] Furthermore, intravenous administration of alpha-CGRP is able to induce headache in individuals susceptible to migraine.[31][26]

Medicines

New medicines are now on the market that contain antibodies against either CGRP itself, or its receptor. They are called monoclonal antibodies (MABs) and are large molecules that do not cross the blood-brain-barrier.[32] They typically are not metabolized by the liver and have little direct impact on the metabolism of more conventional small-molecule drugs.[33] They also tend to have relatively long half-lives in the body, but must be given parenterally (preferably by injection) due to very poor absorption from the digestive tract.[34] They have been proved to be effective in people who experience migraine headaches, both with and without aura, and both episodic and chronic. These are the first class of preventive medications originally designed and approved for people with migraine.[26] Monoclonal means all the antibodies are made from the same genetic material, although different MABs may derive from different sources, e.g. from hamster ovarian cells, from yeast cells or from humanized cell cultures. The antibodies are also made repeatedly to make them all identical, which results in difficult and relatively expensive production lines. Antibodies are proteins that counter or interfere with very specific parts of another protein or the site where a protein is supposed to bind to the receptor. Most commonly thought of in being used to prevent or fight off infections.[35]

The first 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.[36][37]

The second approved by the FDA is called fremanezumab (trade name Ajovy), produced by the Teva pharmaceutical 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.[38][39]

The third approved by the FDA is called galcanezumab (trade name Emgality), produced by the Eli Lilly 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 side effects are injection site reactions.[40][41]

Approved by the FDA in February 2020, ubrogepant is an oral medication manufactured by Allergan.

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

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 other psychotropic cannabinoids cannot do.[42][43]

References
  1. Jia S, Zhang SJ, Wang XD, Yang ZH, Sun YN, Gupta A, et al. (August 2019). "Calcitonin gene-related peptide enhances osteogenic differentiation and recruitment of bone marrow mesenchymal stem cells in rats". Experimental and Therapeutic Medicine. 18 (2): 1039–1046. doi:10.3892/etm.2019.7659. PMC 6601389. PMID 31316600.
  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. Norman A, Henry H, Litwack G (2014). Hormones. Amsterdam: Elsevier. ISBN 978-0-12-369444-7.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. 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.
  15. Schäfers M, Svensson CI, Sommer C, Sorkin LS (April 2003). "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. doi:10.1523/JNEUROSCI.23-07-02517.2003. PMC 6742090. PMID 12684435.
  16. 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.
  17. 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.
  18. 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.
  19. 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.
  20. 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.
  21. 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.
  22. 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.
  23. 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.
  24. 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.
  25. Tepper S. "What to Know About the New CGRP Migraine Treatment Options". American Migraine Foundation. Retrieved 23 February 2019.
  26. 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.
  27. Durham PL (June 2006). "Calcitonin gene-related peptide (CGRP) and migraine". Headache. 46 Suppl 1 (Suppl 1): S3-8. doi:10.1111/j.1526-4610.2006.00483.x. PMC 3134175. PMID 16927957.
  28. 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.
  29. 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.
  30. 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.
  31. Pardridge WM (December 2017). "Delivery of Biologics Across the Blood-Brain Barrier with Molecular Trojan Horse Technology". BioDrugs. 31 (6): 503–519. doi:10.1007/s40259-017-0248-z. PMID 29067674. S2CID 9282946.
  32. Ferri N, Bellosta S, Baldessin L, Boccia D, Racagni G, Corsini A (September 2016). "Pharmacokinetics interactions of monoclonal antibodies". Pharmacological Research. 111: 592–599. doi:10.1016/j.phrs.2016.07.015. PMID 27438459.
  33. 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.
  34. Bank J (2018-01-16). "CGRP: What You Need To Know". National Headache Foundation. Retrieved 23 February 2019.
  35. Rosenberg J (18 May 2018). "FDA Approves Erenumab, First CGRP Inhibitor for Prevention of Migraine". AJMC.com. Retrieved 23 February 2019.
  36. 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.
  37. "FDA Approves Second Anti-CGRP Treatment for Migraines". American Migraine Foundation. Retrieved 23 February 2019.
  38. 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.
  39. "Lilly's Emgality™ (galcanezumab-gnlm) Receives U.S. FDA Approval for the Preventive Treatment of Migraine in Adults". Lilly. Retrieved 23 February 2019.
  40. Lamb YN (November 2018). "Galcanezumab: First Global Approval". Drugs. 78 (16): 1769–1775. doi:10.1007/s40265-018-1002-7. PMID 30378008. S2CID 53107438.
  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.
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