| 词条 | Calcitonin gene-related peptide |
| 释义 |
| Name = calcitonin-related polypeptide alpha | caption = | image = | width = | HGNCid = 1437 | Symbol = CALCA | AltSymbols = CALC1 | EntrezGene = 796 | OMIM = 114130 | RefSeq = NM_001741 | UniProt = P06881 | PDB = | ECnumber = | Chromosome = 11 | Arm = p | Band = 15.2 | LocusSupplementaryData = }}{{infobox protein | Name = calcitonin-related polypeptide, beta | caption = | image = | width = | HGNCid = 1438 | Symbol = CALCB | AltSymbols = CALC2 | EntrezGene = 797 | OMIM = 114160 | RefSeq = NM_000728 | UniProt = P10092 | PDB = | ECnumber = | Chromosome = 11 | Arm = p | Band = 14.2 | LocusSupplementaryData = -p12 }}Calcitonin gene-related peptide (CGRP) is a member of the calcitonin family of peptides, which in humans exists in two forms, α-CGRP and β-CGRP. α-CGRP is a 37-amino acid peptide and is formed from the alternative splicing[1] of the calcitonin/CGRP gene located on chromosome 11. The less-studied β-CGRP differs in three amino acids (in humans) and is encoded in a separate gene in the same vicinity.[2] FunctionCGRP is produced in both peripheral and central neurons.[3] It is a potent peptide vasodilator and can function in the transmission of nociception.[4][5] 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.[6] 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. ReceptorsCGRP 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).[7] CGRP receptors are found throughout 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).[8] The extracellular loop number 2 is fundamental for ligand induced activation, with key interactions of R274/Y278/D280/W283.[9] RegulationRegulation of the calcitonin gene-related peptide (CGRP) gene is in part controlled by the expression of the mitogen-activated protein kinases (MAPK) signaling pathway,[10] cytokines such as TNFα [11] and iNOS.[12] 5HT1 receptor agonists, such as sumatriptan, increase intracellular calcium, which cause decreases in CGRP promoter activity.[10]Research{{further|Calcitonin gene-related peptide receptor antagonist}}{{primary sources|section|date=February 2018}}{{update|section|date=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.[13][14][15][16][17][18] [20] There is mounting evidence to suggest that CGRP may be beneficial in preventing the development of hypertension and cardiovascular pathologies associated with hypertension.[19] 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 than males (7.5%) to endure this debilitative health condition.[20] 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.[21] [20] This CGRP then binds to and activates CGRP receptors located around meningeal vessels, causing vasodilation, mast cell degranulation, and plasma extravasation.[8][21][22][23] 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 plasma drawn from the external jugular vein.[8][21][22][23] Furthermore, intravenous administration of alpha-CGRP is able to induce headache in individuals susceptible to migraine.[24] [20] MedicinesNew medicines are now on the market that create anti-bodies against CGRP and bind to the receptor that the CGRP binds to. They are called monoclonal antibodies (MABs) and are large molecules that do not cross the blood-brain barrier and they are not digested by the liver, which prevents liver toxicity or interactions with other drugs and gives them a longer half-life than many chemical drugs, but must be given parenterally (preferably by injection) to be absorbed properly by the body. They have been proved to be effective in migraine patients both with and without aura, and both episodic and chronic migraineurs. These are the first class of preventive medications originally designed and approved for migraineurs.[25] 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 cell 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.[26] The first approved by the FDA is called Erenumab (trade name Aimovig), produced by pharmaceutical company Amgen and Novartis. It reacts to the CGRP receptor. It is injected once monthly with a dose of 70 or 140MG. Few adverse effects were reported (most related to injection site reactions) and patients had a significant reduction in migraines.[27][28] The second approved by the FDA is called Fremanezumab (trade name Ajovy), produced by the Teva pharmaceutical company. It interacts with the CGRP protein, which's expression is related to migraine attacks. It may be administered monthly or every three months, giving options for users. Trials have showed 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.[29][30] The third approved by the FDA is called Galcanezumab (trade name Emgality), produced by the Eli Lilly Company. It interacts with the CGRP protein, which's 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.[31][32] References1. ^{{cite journal | vauthors = Amara SG, Jonas V, Rosenfeld MG, Ong ES, Evans RM | title = Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products | journal = Nature | volume = 298 | issue = 5871 | pages = 240–4 | date = July 1982 | pmid = 6283379 | doi = 10.1038/298240a0 | bibcode = 1982Natur.298..240A }} 2. ^{{cite journal | vauthors = Rezaeian AH, Isokane T, Nishibori M, Chiba M, Hiraiwa N, Yoshizawa M, Yasue H | title = alphaCGRP and betaCGRP transcript amount in mouse tissues of various developmental stages and their tissue expression sites | journal = Brain & Development | volume = 31 | issue = 9 | pages = 682–93 | date = October 2009 | pmid = 19062206 | doi = 10.1016/j.braindev.2008.10.011 }} 3. ^{{cite journal | vauthors = Rosenfeld MG, Mermod JJ, Amara SG, Swanson LW, Sawchenko PE, Rivier J, Vale WW, Evans RM | title = Production of a novel neuropeptide encoded by the calcitonin gene via tissue-specific RNA processing | journal = Nature | volume = 304 | issue = 5922 | pages = 129–35 | year = 1983 | pmid = 6346105 | doi = 10.1038/304129a0 | bibcode = 1983Natur.304..129R }} 4. ^{{cite journal | vauthors = Brain SD, Williams TJ, Tippins JR, Morris HR, MacIntyre I | title = Calcitonin gene-related peptide is a potent vasodilator | journal = Nature | volume = 313 | issue = 5997 | pages = 54–6 | year = 1985 | pmid = 3917554 | doi = 10.1038/313054a0 | bibcode = 1985Natur.313...54B }} 5. ^{{cite journal | vauthors = McCulloch J, Uddman R, Kingman TA, Edvinsson L | title = Calcitonin gene-related peptide: functional role in cerebrovascular regulation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 83 | issue = 15 | pages = 5731–5 | date = August 1986 | pmid = 3488550 | pmc = 386363 | doi = 10.1073/pnas.83.15.5731 | bibcode = 1986PNAS...83.5731M }} 6. ^{{cite journal | vauthors = Chen LJ, Zhang FG, Li J, Song HX, Zhou LB, Yao BC, Li F, Li WC | title = Expression of calcitonin gene-related peptide in anterior and posterior horns of the spinal cord after brachial plexus injury | journal = Journal of Clinical Neuroscience | volume = 17 | issue = 1 | pages = 87–91 | date = January 2010 | pmid = 19969463 | doi = 10.1016/j.jocn.2009.03.042 }} 7. ^{{cite journal | vauthors = Poyner DR, Sexton PM, Marshall I, Smith DM, Quirion R, Born W, Muff R, Fischer JA, Foord SM | title = International Union of Pharmacology. 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The mammalian calcitonin gene-related peptides, adrenomedullin, amylin, and calcitonin receptors | journal = Pharmacological Reviews | volume = 54 | issue = 2 | pages = 233–46 | date = June 2002 | pmid = 12037140 | doi = 10.1124/pr.54.2.233 }} 8. ^1 2 {{cite journal | vauthors = Arulmani U, Maassenvandenbrink A, Villalón CM, Saxena PR | title = Calcitonin gene-related peptide and its role in migraine pathophysiology | journal = European Journal of Pharmacology | volume = 500 | issue = 1–3 | pages = 315–30 | date = October 2004 | pmid = 15464043 | doi = 10.1016/j.ejphar.2004.07.035 }} 9. ^{{cite journal | vauthors = Woolley MJ, Simms J, Mobarec JC, Reynolds CA, Poyner DR, Conner AC | title = Understanding the molecular functions of the second extracellular loop (ECL2) of the calcitonin gene-related peptide (CGRP) receptor using a comprehensive mutagenesis approach | journal = Molecular and Cellular Endocrinology | volume = 454 | issue = | pages = 39–49 | date = October 2017 | pmid = 28572046 | doi = 10.1016/j.mce.2017.05.034 }} 10. ^1 {{cite journal | vauthors = Durham PL, Russo AF | title = Stimulation of the calcitonin gene-related peptide enhancer by mitogen-activated protein kinases and repression by an antimigraine drug in trigeminal ganglia neurons | journal = The Journal of Neuroscience | volume = 23 | issue = 3 | pages = 807–15 | date = February 2003 | pmid = 12574409 | doi = 10.1523/JNEUROSCI.23-03-00807.2003}} 11. ^{{cite journal | vauthors = Schäfers M, Svensson CI, Sommer C, Sorkin LS | title = Tumor necrosis factor-alpha induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons | journal = The Journal of Neuroscience | volume = 23 | issue = 7 | pages = 2517–21 | date = April 2003 | pmid = 12684435 | doi = 10.1523/JNEUROSCI.23-07-02517.2003}} 12. ^{{cite journal | vauthors = Li J, Vause CV, Durham PL | title = Calcitonin gene-related peptide stimulation of nitric oxide synthesis and release from trigeminal ganglion glial cells | journal = Brain Research | volume = 1196 | issue = | pages = 22–32 | date = February 2008 | pmid = 18221935 | pmc = 2268710 | doi = 10.1016/j.brainres.2007.12.028 }} 13. ^{{cite journal | vauthors = Buzzi MG, Bonamini M, Moskowitz MA | title = Neurogenic model of migraine | journal = Cephalalgia | volume = 15 | issue = 4 | pages = 277–80 | year = 1995 | pmid = 7585923 | doi = 10.1046/j.1468-2982.1995.1504277.x }} 14. ^{{cite journal | vauthors = Goto K, Miyauchi T, Homma S, Ohshima N | title = Calcitonin gene-related peptide in the regulation of cardiac function | journal = Annals of the New York Academy of Sciences | volume = 657 | issue = 1| pages = 194–203 | date = June 1992 | pmid = 1637085 | doi = 10.1111/j.1749-6632.1992.tb22768.x | bibcode = 1992NYASA.657..194G }} 15. ^{{cite journal | vauthors = Joyce CD, Fiscus RR, Wang X, Dries DJ, Morris RC, Prinz RA | title = Calcitonin gene-related peptide levels are elevated in patients with sepsis | journal = Surgery | volume = 108 | issue = 6 | pages = 1097–101 | date = December 1990 | pmid = 2247835 | doi = }} 16. ^{{cite journal | vauthors = Edvinsson L, Goadsby PJ | title = Neuropeptides in migraine and cluster headache | journal = Cephalalgia | volume = 14 | issue = 5 | pages = 320–7 | date = October 1994 | pmid = 7828188 | doi = 10.1046/j.1468-2982.1994.1405320.x }} 17. ^{{cite journal | vauthors = Ferrari MD, Saxena PR | title = On serotonin and migraine: a clinical and pharmacological review | journal = Cephalalgia | volume = 13 | issue = 3 | pages = 151–65 | date = June 1993 | pmid = 8395342 | doi = 10.1046/j.1468-2982.1993.1303151.x }} 18. ^{{cite journal | vauthors = Goadsby PJ, Edvinsson L | title = Human in vivo evidence for trigeminovascular activation in cluster headache. Neuropeptide changes and effects of acute attacks therapies | journal = Brain | volume = 117 ( Pt 3) | issue = 3 | pages = 427–34 | date = June 1994 | pmid = 7518321 | doi = 10.1093/brain/117.3.427 }} 19. ^{{cite journal | vauthors = Russell FA, King R, Smillie SJ, Kodji X, Brain SD | title = Calcitonin gene-related peptide: physiology and pathophysiology | journal = Physiological Reviews | volume = 94 | issue = 4 | pages = 1099–142 | date = October 2014 | pmid = 25287861 | pmc = 4187032 | doi = 10.1152/physrev.00034.2013 }} 20. ^{{cite journal | vauthors = Pellesi L, Guerzoni S, Pini LA | title = Spotlight on Anti-CGRP Monoclonal Antibodies in Migraine: The Clinical Evidence to Date | journal = Clinical Pharmacology in Drug Development | volume = 6 | issue = 6 | pages = 534–547 | date = November 2017 | pmid = 28409893 | pmc = 5697612 | doi = 10.1002/cpdd.345 }} 21. ^1 2 {{cite journal | vauthors = Durham PL | title = Calcitonin gene-related peptide (CGRP) and migraine | journal = Headache | volume = 46 Suppl 1 | issue = Suppl 1 | pages = S3–8 | date = June 2006 | pmid = 16927957 | pmc = 3134175 | doi = 10.1111/j.1526-4610.2006.00483.x }} 22. ^1 {{cite journal | vauthors = Goadsby PJ, Edvinsson L, Ekman R | title = Vasoactive peptide release in the extracerebral circulation of humans during migraine headache | journal = Annals of Neurology | volume = 28 | issue = 2 | pages = 183–7 | date = August 1990 | pmid = 1699472 | doi = 10.1002/ana.410280213 }} 23. ^1 {{cite journal | vauthors = Edvinsson L | title = Neuronal signal substances as biomarkers of migraine | journal = Headache | volume = 46 | issue = 7 | pages = 1088–94 | year = 2006 | pmid = 16866713 | doi = 10.1111/j.1526-4610.2006.00502.x }} 24. ^{{cite journal | vauthors = Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B, Olesen J | title = CGRP may play a causative role in migraine | journal = Cephalalgia | volume = 22 | issue = 1 | pages = 54–61 | date = February 2002 | pmid = 11993614 | doi = 10.1046/j.1468-2982.2002.00310.x }} 25. ^1 2 3 {{cite web |last1=Tepper |first1=Stewart | name-list-format = vanc |title=What to Know About the New CGRP Migraine Treatment Options |url=https://americanmigrainefoundation.org/resource-library/what-to-know-about-the-new-anti-cgrp-migraine-treatment-options/ |website=American Migraine Foundation | accessdate = 23 February 2019}} 26. ^{{cite web |last1=Bank |first1=James | name-list-format = vanc |title=CGRP: What You Need To Know |url=https://headaches.org/2018/01/16/cgrp-need-know/ |website=National Headache Foundation | accessdate = 23 February 2019 |date=2018-01-16 }} 27. ^{{cite web |last1=Rosenberg |first1=Jaime | name-list-format = vanc |title=FDA Approves Erenumab, First CGRP Inhibitor for Prevention of Migraine |url=https://www.ajmc.com/newsroom/fda-approves-erenumab-first-cgrp-inhibitor-for-prevention-of-migraine |website=AJMC.com | accessdate = 23 February 2019 }} 28. ^{{cite journal | vauthors = Lattanzi S, Brigo F, Trinka E, Vernieri F, Corradetti T, Dobran M, Silvestrini M | title = Erenumab for Preventive Treatment of Migraine: A Systematic Review and Meta-Analysis of Efficacy and Safety | journal = Drugs | volume = | issue = | pages = | date = February 2019 | pmid = 30793254 | doi = 10.1007/s40265-019-01069-1 }} 29. ^{{cite web |title=FDA Approves Second Anti-CGRP Treatment for Migraines |url=https://americanmigrainefoundation.org/resource-library/fda-approves-second-anti-cgrp-treatment-for-migraine/ |website=American Migraine Foundation | accessdate = 23 February 2019 }} 30. ^{{cite journal | vauthors = Bigal ME, Rapoport AM, Silberstein SD, Walter S, Hargreaves RJ, Aycardi E | title = From LBR-101 to Fremanezumab for Migraine | journal = CNS Drugs | volume = 32 | issue = 11 | pages = 1025–1037 | date = November 2018 | pmid = 30311143 | doi = 10.1007/s40263-018-0579-4 }} 31. ^{{cite web |title=Lilly's Emgality™ (galcanezumab-gnlm) Receives U.S. FDA Approval for the Preventive Treatment of Migraine in Adults |url=https://investor.lilly.com/news-releases/news-release-details/lillys-emgalitytm-galcanezumab-gnlm-receives-us-fda-approval |website=Lilly | accessdate = 23 February 2019 }} 32. ^{{cite journal | vauthors = Lamb YN | title = Galcanezumab: First Global Approval | journal = Drugs | volume = 78 | issue = 16 | pages = 1769–1775 | date = November 2018 | pmid = 30378008 | doi = 10.1007/s40265-018-1002-7 }} External links
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