Calcitonin gene-related peptide: Difference between revisions

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'''Calcitonin gene-related peptide''' ('''CGRP''') is a member of the [[calcitonin]] family of [[peptide]]s, 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]]<ref>{{cite journal|last1=Amara|first1=SG|last2=Jonas|first2=V|last3=Rosenfeld|first3=MG|last4=Ong|first4=ES|last5=Evans|first5=RM|title=Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products.|journal=Nature|date=15 July 1982|volume=298|issue=5871|pages=240–4|pmid=6283379|doi=10.1038/298240a0}}</ref> 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.<ref name="pmid19062206">{{cite journal |author= Rezaelan, A.H.|title= AlphaCGRP and betaCGRP transcript amount in mouse tissues of various developmental stages and their tissue expression sites |journal=Brain and Development |volume=31 |issue=9 |pages=682–693 |year=2009 |pmid=19062206 |doi= 10.1016/j.braindev.2008.10.011 |url=|display-authors=etal}}</ref>
'''Calcitonin gene-related peptide''' ('''CGRP''') is a member of the [[calcitonin]] family of [[peptide]]s, 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]]<ref>{{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 }}</ref> 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.<ref name="pmid19062206">{{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 }}</ref>


== Function ==
== Function ==


CGRP is produced in both peripheral and central [[neurons]].<ref name="pmid6346105">{{cite journal |author= Rosenfeld, M.|title= Production of a novel neuropeptide encoded by the calcitonin gene via tissue-specific RNA processing |journal=Nature |volume=304 |issue=5922 |pages=129–135 |year=1983 |pmid=6346105 |doi= 10.1038/304129a0|url=|display-authors=etal}}</ref> It is a potent peptide [[vasodilator]] and can function in the transmission of pain.<ref name="pmid3917554">{{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|url=}}</ref><ref name="pmid3488550">{{cite journal |author= McCulloch, J.|title= Calcitonin gene-related peptide: functional role in cerebrovascular regulation |journal= Proc Natl Acad Sci USA |volume=83 |pages=5731–5735 |year=1986 |pmid=3488550 |doi= 10.1073/pnas.83.15.5731|url= |issue= 15 |pmc= 386363|display-authors=etal}}</ref> 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.<ref name="pmid19969463">{{cite journal |vauthors=Chen LJ, Zhang FG, Li J | title = Expression of calcitonin gene-related peptide in ventral and dorosal horns of the spinal cord after brachial plexus injury | journal = J Clin Neurosci | volume = 17 | issue = 1 | pages = 87–91 |date=January 2010 | pmid = 19969463 | doi = 10.1016/j.jocn.2009.03.042 | url = |display-authors=etal}}</ref> 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]].
CGRP is produced in both peripheral and central [[neurons]].<ref name="pmid6346105">{{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 }}</ref> It is a potent peptide [[vasodilator]] and can function in the transmission of [[nociception]].<ref name="pmid3917554">{{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 }}</ref><ref name="pmid3488550">{{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 }}</ref> 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.<ref name="pmid19969463">{{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 }}</ref> 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]].


== Receptors ==
== Receptors ==


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]]).<ref name="pmid12037140">{{cite journal |author= Poyner, D.|title= International Union of Pharmacology. XXXII. The mammalian calcitonin gene-related peptides, adrenomedullin, amylin, and calcitonin receptors|journal= Pharmacol Rev |volume=54 |issue=2 |pages=233–246 |year=2002 |pmid=12037140 |doi= 10.1124/pr.54.2.233|url=|display-authors=etal}}</ref> [[CALCRL|CGRP receptor]]s are found throughout the body, suggesting that the protein may modulate a variety of physiological functions in all major systems (e.g., [[respiratory system|respiratory]], [[endocrine system|endocrine]], [[gastrointestinal system|gastrointestinal]], [[immune system|immune]], and [[cardiovascular system|cardiovascular]]).<ref name="pmid15464043">{{cite journal |author= Arulmani, U. |journal= Eur J Pharmacol |volume=500 |issue=1–3|pages=315–30 |year=2004 |pmid=15464043 |doi= 10.1016/j.ejphar.2004.07.035|url= |title= Calcitonin gene-related peptide and its role in migraine pathophysiology|display-authors=etal}}</ref> The extracellular loop number 2 is fundamental for ligand induced activation, with key interactions of R274/Y278/D280/W283.<ref name="pmid28572046">{{cite journal |author= Woolley, MJ. |author2= Simms, J. |author3= Mobarec, J.C. |author4= Reynolds, C.A. |author5= Poyner, D. |author6= Conner, A.C. |journal= Mol Cell Endocrinol |issue= |pages= |year=2017 |pmid=28572046 |doi= 10.1016/j.mce.2017.05.034|url= |title= Understanding the molecular functions of the second extracellular loop (ECL2) of the calcitonin gene-related peptide (CGRP) receptor using a comprehensive mutagenesis approach|display-authors=etal}}</ref>
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]]).<ref name="pmid12037140">{{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. XXXII. 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 }}</ref> [[CALCRL|CGRP receptor]]s are found throughout the body, suggesting that the protein may modulate a variety of physiological functions in all major systems (e.g., [[respiratory system|respiratory]], [[endocrine system|endocrine]], [[gastrointestinal system|gastrointestinal]], [[immune system|immune]], and [[cardiovascular system|cardiovascular]]).<ref name="pmid15464043">{{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 }}</ref> The extracellular loop number 2 is fundamental for ligand induced activation, with key interactions of R274/Y278/D280/W283.<ref name="pmid28572046">{{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 }}</ref>


== Regulation ==
== Regulation ==


Regulation of the calcitonin gene-related peptide (CGRP) gene is in part controlled by the expression of the [[MAPK signaling pathway|mitogen-activated protein kinases (MAPK) signaling pathway]],<ref name="pmid12574409">{{cite journal |author1=Durham, P.  |author2=A. Russo |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= J Neurosci |volume=23 |issue=3 |pages=807–815 |year=2003 |pmid=12574409 |doi= |url=}}</ref> [[cytokines]] such as [[TNFα]] <ref name="pmid12684435">{{cite journal |author= Schafers, M.|title= Tumor necrosis factor-alpha induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons |journal= J Neurosci |volume=23 |issue=7 |pages=2517–21 |year=2003 |pmid=12684435 |doi= |url=|display-authors=etal}}</ref> and [[iNOS]].<ref name="pmid18221935">{{cite journal |author= Li, J. |author2=C. Vause |author3=P. Durham |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 |year=2008 |pmid=18221935 |doi= 10.1016/j.brainres.2007.12.028|url= |pmc= 2268710}}</ref>
Regulation of the calcitonin gene-related peptide (CGRP) gene is in part controlled by the expression of the [[MAPK signaling pathway|mitogen-activated protein kinases (MAPK) signaling pathway]],<ref name="pmid12574409">{{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 = }}</ref> [[cytokines]] such as [[TNFα]] <ref name="pmid12684435">{{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 = }}</ref> and [[iNOS]].<ref name="pmid18221935">{{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 }}</ref>


[[5-HT1 receptor|5HT1]] receptor [[agonists]], such as [[sumatriptan]], increase intracellular calcium, which cause decreases in CGRP promoter activity.<ref name="pmid12574409"/>
[[5-HT1 receptor|5HT1]] receptor [[agonists]], such as [[sumatriptan]], increase intracellular calcium, which cause decreases in CGRP promoter activity.<ref name="pmid12574409"/>


== Clinical significance ==
== Research ==
{{further|Calcitonin gene-related peptide receptor antagonist}}
{{further|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.<ref name="pmid7585923">{{cite journal |author= Buzzi, M. |author2=M. Bonamini |author3=M. Moskowitz |journal= Cephalalgia |volume=15 |issue=4 |pages=277–280 |year=1995 |pmid=7585923 |doi= 10.1046/j.1468-2982.1995.1504277.x|url= |title= Neurogenic model of migraine}}</ref><ref name="pmid1637085">{{cite journal |author= Goto, K. |journal= Ann NY Acad Sci |volume= 657|issue= |pages=194–203 |year=1992 |pmid=1637085 |doi= 10.1111/j.1749-6632.1992.tb22768.x|url= |title= Calcitonin gene-related peptide in the regulation of cardiac function|display-authors=etal}}</ref><ref name="pmid2247835">{{cite journal |author= Joyce, C.|title= Calcitonin gene-related peptide levels are elevated in patients with sepsis |journal=Surgery |volume=108 |issue=6 |pages=1097–101 |year=1990 |pmid=2247835 |doi= |url=|display-authors=etal}}</ref><ref name="pmid7828188">{{cite journal |author1=Edvinsson, L.  |author2=P. Goadsby |title= Neuropeptides in migraine and cluster headache |journal= Cephalalgia |volume=14 |issue=5 |pages=320–7 |year=1994 |pmid=7828188 |doi= 10.1046/j.1468-2982.1994.1405320.x|url=}}</ref><ref name="pmid8395342">{{cite journal |author1=Ferrari, M.  |author2=P. Saxena |title= On serotonin and migraine: a clinical and pharmacological review |journal= Cephalalgia |volume=13 |issue=3 |pages=151–65 |year=1993 |pmid=8395342 |doi= 10.1046/j.1468-2982.1993.1303151.x|url=}}</ref><ref name="pmid7518321">{{cite journal |author1=Goadsby, P.  |author2=L. Edvinsson |title= Human in vivo evidence for trigeminovascular activation in cluster headache. Neuropeptide changes and effects of acute attacks therapies |journal= Brain |volume=117 |issue= 3|pages=427–34 |year=1993 |pmid=7518321 |doi= 10.1093/brain/117.3.427|url=}}</ref>  
{{primary|section|date=February 2018}}
{{outdated|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.<ref name="pmid7585923">{{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 }}</ref><ref name="pmid1637085">{{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 = | pages = 194–203 | date = June 1992 | pmid = 1637085 | doi = 10.1111/j.1749-6632.1992.tb22768.x }}</ref><ref name="pmid2247835">{{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 = }}</ref><ref name="pmid7828188">{{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 }}</ref><ref name="pmid8395342">{{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 }}</ref><ref name="pmid7518321">{{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 }}</ref>  


There is mounting evidence to suggest that CGRP is ''beneficial'' in preventing the development of hypertension and cardiovascular pathologies associated with hypertension.<ref>{{Cite journal|title = Calcitonin Gene-Related Peptide: Physiology and Pathophysiology|url = http://physrev.physiology.org/content/94/4/1099 |journal = Physiological Reviews|date = 2014-10-01|access-date = 2015-04-17|issn = 0031-9333|pmid = 25287861|pages = 1099–1142|volume = 94|issue = 4|doi = 10.1152/physrev.00034.2013|first = F. A.|last = Russell|first2 = R.|last2 = King|first3 = S.-J.|last3 = Smillie|first4 = X.|last4 = Kodji|first5 = S. D.|last5 = Brain|pmc=4187032}}</ref> Recently a study has been published investigating the protective role of alpha-CGRP in an animal model of hypertension by use of alpha-CGRP knockout mice. Here, the authors show that mice lacking alpha-CGRP gene progress to develop significantly worse hypertension, vascular fibrosis and vascular inflammation attributable to a pro-oxidant milieu.<ref>{{Cite journal|title = An Ongoing Role of α-Calcitonin Gene–Related Peptide as Part of a Protective Network Against Hypertension, Vascular Hypertrophy, and Oxidative Stress|url = http://hyper.ahajournals.org/content/63/5/1056 |journal = Hypertension|date = 05/01/2014|access-date = 2015-04-17|issn = 0194-911X|pmid = 24516108|pages = 1056–1062|volume = 63|issue = 5|doi = 10.1161/HYPERTENSIONAHA.113.02517|first = Sarah-Jane|last = Smillie|first2 = Ross|last2 = King|first3 = Xenia|last3 = Kodji|first4 = Emilie|last4 = Outzen|first5 = Gabor|last5 = Pozsgai|first6 = Elizabeth|last6 = Fernandes|first7 = Nichola|last7 = Marshall|first8 = Patricia de|last8 = Winter|first9 = Richard J.|last9 = Heads}}</ref>
There is mounting evidence to suggest that CGRP may be ''beneficial'' in preventing the development of hypertension and cardiovascular pathologies associated with hypertension.<ref>{{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 | url = http://physrev.physiology.org/content/94/4/1099 | access-date = 2015-04-17 }}</ref>  


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]].<ref name="pmid16927957">{{cite journal |author= Durham, P |title= Calcitonin Gene-Related Peptide (CGRP) and Migraine |journal= Headache |volume=48 |issue= Suppl 1|pages= S3–8|year=2006 |pmid=16927957 |doi= 10.1111/j.1526-4610.2006.00483.x|url= |pmc= 3134175}}</ref> This CGRP then binds to and activates CGRP receptors located around meningeal vessels, causing vasodilation, [[mast cell]] degranulation, and plasma extravasation.<ref name="pmid15464043"/><ref name="pmid16927957"/><ref name="pmid1699472">{{cite journal |author= Goadsby, P. |author2=L. Edvinsson |author3=R. Elkman |title= Vasoactive peptide release in the extracerebral circulation of humans during migraine headache |journal= Ann Neurol |volume=28 |issue=2 |pages= 183–7|year=1990 |pmid= 1699472 |doi= 10.1002/ana.410280213|url=}}</ref><ref name="pmid16866713">{{cite journal |author= 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|url=}}</ref> 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.<ref name="pmid15464043"/><ref name="pmid16927957"/><ref name="pmid1699472"/><ref name="pmid16866713"/> Furthermore, intravenous administration of alpha-CGRP is able to induce headache in individuals susceptible to migraine.<ref name="pmid11993614">{{cite journal |author= Lassen, L.|title= CGRP may play a causative role in migraine |journal= Cephalalgia |volume=22 |issue=1 |pages=54–61|year=2002 |pmid=11993614 |doi= 10.1046/j.1468-2982.2002.00310.x|url=|display-authors=etal}}</ref>
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]].<ref name="pmid16927957">{{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 }}</ref> This CGRP then binds to and activates CGRP receptors located around meningeal vessels, causing vasodilation, [[mast cell]] degranulation, and plasma extravasation.<ref name="pmid15464043"/><ref name="pmid16927957"/><ref name="pmid1699472">{{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 }}</ref><ref name="pmid16866713">{{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 }}</ref> 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.<ref name="pmid15464043"/><ref name="pmid16927957"/><ref name="pmid1699472"/><ref name="pmid16866713"/> Furthermore, intravenous administration of alpha-CGRP is able to induce headache in individuals susceptible to migraine.<ref name="pmid11993614">{{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 }}</ref>


The source of CGRP in [[migraine]] (and other pain conditions) is largely thought to derive from the peptidergic peripheral innervation where alpha-CGRP is the predominant isoform produced by sensory neurons. It is the alpha-CGRP isoform that is presumed to be the primary contributor to pain mechanisms. However, more recent evidence demonstrates that CGRP is expressed among [[keratinocytes]] of the [[epidermis (skin)|epidermis]] where it is predominantly the beta form.<ref name="pmid21641113">{{cite journal |vauthors=Hou Q, Barr T, Gee L, Vickers J, Wymer J, Borsani E, Rodella L, Getsios S, Burdo T, Eisenberg E, Guha U, Lavker R, Kessler J, Chittur S, Fiorino D, Rice F, Albrecht P | title = Keratinocyte Expression of CGRPβ: Implications for Neuropathic and Inflammatory Pain Mechanisms | journal = Pain | volume = 152| issue = 9| pages = 2036–51|date=June 2011 | pmid = 21641113 | doi = 10.1016/j.pain.2011.04.033 | pmc = 3157543 }}</ref> Furthermore, CGRP expression in keratinocytes is substantially increased in certain human chronic pain conditions and animal models of induced chronic pain conditions, whereas the alpha-CGRP containing peptidergic innervation is decreased in painful skin sites.<ref name="pmid21641113"/> Therefore, keratinocyte-derived beta-CGRP may have an important role in [[chronic pain]] mechanisms, as well as other dermatologic disorders known to involve changes in CGRP levels, such as psoriasis. Although very little is known about the functional differences between these two isoforms, research has demonstrated that the beta-CGRP is also expressed among enteric neurons of the gut, and CGRP has been implicated in mechanisms of visceral pain disorders, such as [[irritable bowel syndrome]].
== References ==
 
===As a drug target===
[[Botulinum toxin]] type A is able to prevent stimulated release of CGRP through the cleavage of [[SNAP-25]] protein.<ref name="pmid14979881">{{cite journal |author= Durham, P. |author2=R. Cady |author3=R. Cady |title= Regulation of calcitonin gene-related peptide secretion from trigeminal nerve cells by botulinum toxin type A: implications for migraine therapy |journal= Headache |volume=44 |issue=1 |pages=35–42 |year=2004 |pmid=14979881 |doi= 10.1111/j.1526-4610.2004.04007.x|url=}}</ref> Receptor antagonists may also have the potential of limiting the effects of CGRP, though one promising drug candidate in this class ([[telcagepant]]) was withdrawn<ref>[http://www.merck.com/newsroom/news-release-archive/financial/2011_0729.html Merck Announces Second Quarter 2011 Financial Results]</ref> by Merck Pharmaceuticals after phase III trials.<ref name="pmid18808506">{{cite journal |author1=Tepper, S.J.  |author2=M.J. Stillman |title= Clinical and preclinical rationale for CGRP-receptor antagonists in the treatment of migraine |journal= Headache |volume=48 |issue=8 |pages= 1259–68 |year=2008 |pmid=18808506 |doi= 10.1111/j.1526-4610.2008.01214.x|url=}}</ref>
 
[[Fremanezumab]], a humanized [[monoclonal antibody]] directed against CGRP alpha and beta, is in phase III clinical trials for [[cluster headache]]/[[migraine]].<ref>[https://clinicaltrials.gov/ct2/show/NCT02964338 ''A Study Comparing the Efficacy and Safety of TEV-48125 (Fremanezumab) for the Prevention of Chronic Cluster Headache (CCH)'']</ref><ref>[https://clinicaltrials.gov/ct2/show/NCT02945046 ''A Study to Evaluate the Efficacy and Safety of TEV-48125 (Fremanezumab) for the Prevention of Episodic Cluster Headache (ECH)'']</ref><ref name=Kronemyer>[http://www.pharmacypracticenews.com/Web-Only/Article/11-17/Fremanezumab-for-Migraine-Shows-Impressive-Results/45326/ses=ogst?enl=true ''Fremanezumab for Migraine Shows Impressive Results'' Nov 2017]</ref>
 
==References==
{{Reflist|colwidth = 30em}}
{{Reflist|colwidth = 30em}}


==External links==
== External links ==
* {{MeshName|Calcitonin+Gene-Related+Peptide}}
* {{MeshName|Calcitonin+Gene-Related+Peptide}}


Revision as of 20:24, 13 November 2018

calcitonin-related polypeptide alpha
Identifiers
SymbolCALCA
Alt. symbolsCALC1
Entrez796
HUGO1437
OMIM114130
RefSeqNM_001741
UniProtP06881
Other data
LocusChr. 11 p15.2
calcitonin-related polypeptide, beta
Identifiers
SymbolCALCB
Alt. symbolsCALC2
Entrez797
HUGO1438
OMIM114160
RefSeqNM_000728
UniProtP10092
Other data
LocusChr. 11 p14.2-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]

Function

CGRP 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.

Receptors

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).[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]

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,[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 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.[13][14][15][16][17][18]

There is mounting evidence to suggest that CGRP may be beneficial in preventing the development of hypertension and cardiovascular pathologies associated with hypertension.[19]

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.[20] This CGRP then binds to and activates CGRP receptors located around meningeal vessels, causing vasodilation, mast cell degranulation, and plasma extravasation.[8][20][21][22] 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][20][21][22] Furthermore, intravenous administration of alpha-CGRP is able to induce headache in individuals susceptible to migraine.[23]

References

  1. ↑ 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. doi:10.1038/298240a0. PMID 6283379.
  2. ↑ 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.
  3. ↑ Rosenfeld MG, Mermod JJ, Amara SG, Swanson LW, Sawchenko PE, Rivier J, Vale WW, Evans RM (1983). "Production of a novel neuropeptide encoded by the calcitonin gene via tissue-specific RNA processing". Nature. 304 (5922): 129–35. doi:10.1038/304129a0. PMID 6346105.
  4. ↑ Brain SD, Williams TJ, Tippins JR, Morris HR, MacIntyre I (1985). "Calcitonin gene-related peptide is a potent vasodilator". Nature. 313 (5997): 54–6. doi:10.1038/313054a0. PMID 3917554.
  5. ↑ 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. doi:10.1073/pnas.83.15.5731. PMC 386363. PMID 3488550.
  6. ↑ Chen LJ, Zhang FG, Li J, Song HX, Zhou LB, Yao BC, Li F, Li WC (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.
  7. ↑ Poyner DR, Sexton PM, Marshall I, Smith DM, Quirion R, Born W, Muff R, Fischer JA, Foord SM (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.
  8. ↑ 8.0 8.1 8.2 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.
  9. ↑ 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". Molecular and Cellular Endocrinology. 454: 39–49. doi:10.1016/j.mce.2017.05.034. PMID 28572046.
  10. ↑ 10.0 10.1 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. PMID 12574409.
  11. ↑ 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. PMID 12684435.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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: 194–203. doi:10.1111/j.1749-6632.1992.tb22768.x. PMID 1637085.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ Russell FA, King R, Smillie SJ, Kodji X, Brain SD (October 2014). "Calcitonin gene-related peptide: physiology and pathophysiology". Physiological Reviews. 94 (4): 1099–142. doi:10.1152/physrev.00034.2013. PMC 4187032. PMID 25287861. Retrieved 2015-04-17.
  20. ↑ 20.0 20.1 20.2 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.
  21. ↑ 21.0 21.1 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.
  22. ↑ 22.0 22.1 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.
  23. ↑ 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.

External links

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