| Calcitonin-related polypeptide alpha | |||||||
|---|---|---|---|---|---|---|---|
 Human calcitonin (black) bound to thecalcitonin 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. 11p15.2{{{LocusSupplementaryData}}} | ||||||
| |||||||
| 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. 11p15.2{{{LocusSupplementaryData}}} | ||||||
| |||||||
Calcitonin gene-related peptide (CGRP) is aneuropeptide that belongs to thecalcitonin family.[1] Human CGRP consists of twoisoforms, CGRP alpha (α-CGRP, also known as CGRP I) and CGRP beta (β-CGRP, also known as CGRP II).[2] α-CGRP is a 37-amino acid neuropeptide formed byalternative splicing[3] of the calcitonin/CGRP gene located onchromosome 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), andamylin (AMY).[5]
CGRP is produced in both peripheral and centralneurons.[6] It is a potent peptidevasodilator and can function in the transmission ofnociception.[7][8] In thespinal cord, the function and expression of CGRP may differ depending on the location of synthesis. CGRP is derived mainly from the cell bodies ofmotor neurons when synthesized in theventral horn of the spinal cord and may contribute to the regeneration of nervous tissue after injury. Conversely, CGRP is derived fromdorsal root ganglion when synthesized in thedorsal horn of the spinal cord and may be linked to the transmission ofpain.[9] In the trigeminal vascular system, the cell bodies of thetrigeminal 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 achronotrope by increasingheart rate.[10]: 202 Apart from these attributes, CGRP is known to modulate theautonomic 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 anappetite suppressant and contributes togastric acid secretion.[10] It also functions intemperature homeostasis, increases heart rate, and plays a role in the release of thepituitary hormones in aparacrine manner.[10] Because of these characteristics, it has been said that CGRP functions more as aneurotransmitter than a hormone.[10]
CGRP has a role in humanstem cell (HSC) mobilization.[11] In investigations carried out in 2021, treatment with CGRP resulted in significantly increased CGRP levels in thebone marrow extracellular fluid and substantially increased the number of HSCs mobilized bygranulocyte 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 thereceptor activity-modifying protein 1 (RAMP1) pathway.[12]
CGRP mediates its effects through aheteromeric receptor composed of aG 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, andcardiovascular).[14] Thesetransmembrane receptors form folded accordion-like structures embedded in thecell 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 themitogen-activated protein kinase (MAPK)signaling pathway andcytokines likeTNFα andiNOS.[16][17][18]5HT1 receptoragonists likesumatriptan 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 sectionrelies excessively onreferences toprimary sources. Please improve this section by addingsecondary or tertiary sources. Find sources: "Calcitonin gene-related peptide" – news ·newspapers ·books ·scholar ·JSTOR(February 2018) (Learn how and when to remove this message) |
 | This section needs to beupdated. Please help update this article to reflect recent events or newly available information.(February 2018) |
Increased levels of CGRP have been reported inmigraine andtemporomandibular joint disorder patients as well as a variety of other diseases such as cardiac failure, hypertension, and sepsis.[21][22][23][24][25][26][27]
There is mounting evidence to suggest that CGRP may be beneficial in preventing the development of hypertension and cardiovascular pathologies associated with hypertension.[2] This is of particular concern, as females (16.6%) are more genetically predisposed to migraine than are males (7.5%).[28]
Preclinical evidence suggests that, during amigraine, activated primary sensory neurons (meningeal nociceptors) in thetrigeminal ganglion release CGRP from their peripherally projecting nerve endings located within themeninges.[29][27] This CGRP then binds to and activates CGRP receptors located around meningeal vessels, causing vasodilation,mast cell degranulation, and plasmaextravasation.[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 onmonoclonal antibodies have been produced related to CGRP orCGRP 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] Due to the nature of the monoclonal antibodies, they must be administeredparenterally, preferably by injection.[33]
The first CGRP related medication approved by the FDA is callederenumab (trade name Aimovig), produced by pharmaceutical companyAmgen andNovartis. 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 calledfremanezumab (trade name Ajovy), produced by theTeva 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 calledgalcanezumab (trade name Emgality), produced by theEli 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 side effects are injection site reactions.[38][39]
Approved by the FDA in February 2020,ubrogepant (Ubrelvy) is an oral medication manufactured byAbbVie.
Also FDA approved in February 2020,eptinezumab (Vyapti), is an intravenous migraine prophylactic medication manufactured byLundbeck.
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 byPfizer.
In September 2021 the FDA approvedQulipta (atogepant), the first oral CGRP receptor antagonist approved to prevent chronic migraine.[41]
Thephytocannabinoids delta-9tetrahydrocannabinol (Δ9-THC) and itsoxidative byproductcannabinol (CBN) are found to induce aCB1 andCB2cannabinoid receptor-independent release of calcitonin gene-related peptide fromcapsaicin-sensitiveperivascularsensory nerves, an action that other psychotropic cannabinoids cannot do.[42][43]