Calcitonin gene-related peptide
|calcitonin-related polypeptide alpha|
|Locus||Chr. 11 p15.2|
|calcitonin-related polypeptide, beta|
|Locus||Chr. 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 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.
CGRP is produced in both peripheral and central neurons. It is a potent peptide vasodilator and can function in the transmission of nociception. 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. 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 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). 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). The extracellular loop number 2 is fundamental for ligand induced activation, with key interactions of R274/Y278/D280/W283.
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, cytokines such as TNFα  and iNOS.
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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. 
There is mounting evidence to suggest that CGRP may be beneficial in preventing the development of hypertension and cardiovascular pathologies associated with hypertension. 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.
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.  This CGRP then binds to and activates CGRP receptors located around meningeal vessels, causing vasodilation, mast cell degranulation, and plasma extravasation. 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. Furthermore, intravenous administration of alpha-CGRP is able to induce headache in individuals susceptible to migraine. 
New 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. 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.
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.
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.
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.
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