Calcitonin gene-related peptide

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.

Function
CGRP is produced in both peripheral and central neurons. It is a potent peptide vasodilator and can function in the transmission of pain. 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.

Receptors
CGRP mediates its effects though 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).

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, cytokines such as TNFα and iNOS.

5HT1 receptor agonists, such as sumatriptan, increase intracellular calcium, which cause decreases in CGRP promoter activity. Botulinum toxin type A is able to prevent stimulated release of CGRP through the cleavage of SNAP-25 protein. Receptor antagonists may also have the potential of limiting the effects of CGRP, though one promising drug candidate in this class (telcagepant) was withdrawn by Merck Pharmaceuticals after phase III trials.

Clinical significance
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.

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.

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 where it is predominantly the beta form. 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. 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.