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 and calcitonin‑receptor‑stimulating peptide. 

Calcitonin is mainly produced by thyroid C cells.

CGRP is secreted and stored in the nervous system.

The CGRP exists in two forms: CGRP alpha, and CGRP beta.

α-CGRP is a 37-amino acid neuropeptide and is formed by alternative splicing of the calcitonin/CGRP gene located on chromosome 11. 

β-CGRP differs from α-CGRP by three amino acids and is encoded in a separate, nearby gene. 

The CGRP family includes calcitonin, adrenomedullin, and amylin.

CGRP is produced in both peripheral and central neurons.

CGRP is a potent peptide vasodilator and can function in the transmission of nociception.

CGRP is derived mainly from the cell bodies of motor neurons.

When synthesized in the ventral horn of the spinal cord they may contribute to the regeneration of nervous tissue after injury. 

When CGRP comes from dorsal root ganglion, synthesized in the dorsal horn of the spinal cord and may be linked to the transmission of pain.

In the trigeminal vascular system, the trigeminal ganglion cell bodies 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.

CGRP is known to modulate the autonomic nervous system and plays a role in ingestion.

CGRP has moderate effects on calcium homeostasis.

CGRP neoreptide acts as an appetite suppressant and contributes to gastric acid secretion.

Functions in temperature homeostasis, increases heart rate, and plays a role in the release of the pituitary hormones in a paracrine manner.

CGRP functions more as a neurotransmitter than a hormone.

CGRP has a role in human stem cells mobilization. 

G-CSF-induced HSC mobilization is regulated by the nociceptor nerve-derived neuropeptide CGRP. 

CGRP mediates its effects  through a G protein-coupled receptor called calcitonin receptor-like receptor (CALCRL) and a receptor activity-modifying protein (RAMP1).

CGRP receptors are found throughout all the body, suggesting that the protein may modulate a variety of physiological functions in the respiratory, endocrine, gastrointestinal, immune, and cardiovascular systems.

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 inducible nitrous oxide synthetase.

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

CGRP receptor is found in myelinated A-fibers axon.

The CGRP receptor has three subunits: receptor activity-modifying protein 1 (RAMP1), calcitonin-like receptor (CLR) and receptor component protein (RCP).

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.

Evidence suggests 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.

Evidence suggests that, during a migraine, activated primary sensory neurons in the trigeminal ganglion release CGRP from their peripherally projecting nerve endings located within the meninges.

CGRP then binds to and activates CGRP receptors located around meningeal vessels, causing vasodilation, mast cell degranulation, and plasma extravasation.

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.

Furthermore, intravenous administration of alpha-CGRP is able to induce headache in individuals susceptible to migraine.

CGRP is believed to cause sensitization of trigeminal nociceptive neurons, contributing to the pain experienced in migraine.

Monoclonal antibodies (MABs) to CGRP itself, or its receptor and are large molecules that do not cross the blood-brain-barrier, have been proved to be effective in people who experience migraine headaches, both with and without aura, and both episodic and chronic.

Monoclonal antibodies (MABs) to CGRP include: erenumab, fremanezumab, galcanezumab, ubrogepan, and eptinezumab.

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