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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.[1]


CGRP is produced in both peripheral and central neurons.[2] It is a potent peptide vasodilator and can function in the transmission of pain.[3][4] 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.[5] 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 though a heteromeric receptor composed of a G protein-coupled receptor called calcitonin receptor-like receptor (CALCRL) and a receptor activity-modifying protein (RAMP1).[6] 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).[7]


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,[8] cytokines such as TNFα [9] and iNOS.[10]

5HT1 receptor agonists, such as sumatriptan, increase intracellular calcium, which cause decreases in CGRP promoter activity.[8] Botulinum toxin type A is able to prevent stimulated release of CGRP through the cleavage of SNAP-25 protein.[11] Receptor antagonists may also have the potential of limiting the effects of CGRP, though one promising drug candidate in this class (telcagepant) was withdrawn[12] by Merck Pharmaceuticals after phase III trials.[13]

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.[14][15][16][17][18][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.[7][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.[7][20][21][22] Furthermore intravenous administration of alpha-CGRP is able to induce headache in individuals susceptible to migraine.[23]

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.[24] 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.[24] 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.

See also


  1. Rezaelan, A.H., et al. (2009). AlphaCGRP and betaCGRP transcript amount in mouse tissues of various developmental stages and their tissue expression sites. Brain and Development 31 (9): 682–693.
  2. Rosenfeld, M., et al. (1983). Production of a novel neuropeptide encoded by the calcitonin gene via tissue-specific RNA processing. Nature 304 (5922): 129–135.
  3. Brain SD, Williams TJ, Tippins JR, Morris HR, MacIntyre I (1985). Calcitonin gene-related peptide is a potent vasodilator. Nature 313 (5997): 54–6.
  4. McCulloch, J., et al. (1986). Calcitonin gene-related peptide: functional role in cerebrovascular regulation. Proc Natl Acad Sci USA 83 (15): 5731–5735.
  5. Chen LJ, Zhang FG, Li J, et al. (January 2010). Expression of calcitonin gene-related peptide in ventral and dorosal horns of the spinal cord after brachial plexus injury. J Clin Neurosci 17 (1): 87–91.
  6. Poyner, D., et al. (2002). International Union of Pharmacology. XXXII. The mammalian calcitonin gene-related peptides, adrenomedullin, amylin, and calcitonin receptors. Pharmacol Rev 54 (2): 233–246.
  7. 7.0 7.1 7.2 Arulmani, U., et al. (2004). Calcitonin gene-related peptide and its role in migraine pathophysiology. Eur J Pharmacol 500 (1–3): 315–30.
  8. 8.0 8.1 Durham, P. and A. Russo (2003). Stimulation of the calcitonin gene-related peptide enhancer by mitogen-activated protein kinases and repression by an antimigraine drug in trigeminal ganglia neurons. J Neurosci 23 (3): 807–815.
  9. Schafers, M., et al. (2003). Tumor necrosis factor-alpha induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons. J Neurosci 23 (7): 2517–21.
  10. Li, J., C. Vause, and P. Durham (2008). Calcitonin gene-related peptide stimulation of nitric oxide synthesis and release from trigeminal ganglion glial cells. Brain Research 1196: 22–32.
  11. Durham, P., R. Cady, and R. Cady (2004). Regulation of calcitonin gene-related peptide secretion from trigeminal nerve cells by botulinum toxin type A: implications for migraine therapy. Headache 44 (1): 35–42.
  12. Merck Announces Second Quarter 2011 Financial Results
  13. Tepper, S.J. and M.J. Stillman (2008). Clinical and preclinical rationale for CGRP-receptor antagonists in the treatment of migraine. Headache 48 (8): 1259–68.
  14. Buzzi, M., M. Bonamini, and M. Moskowitz (1995). Neurogenic model of migraine. Cephalgia 15 (4): 277–280.
  15. Goto, K., et al. (1992). Calcitonin gene-related peptide in the regulation of cardiac function. Ann NY Acad Sci 267: 194–203.
  16. Joyce, C., et al. (1990). Calcitonin gene-related peptide levels are elevated in patients with sepsis. Surgery 108 (6): 1097–101.
  17. Edvinsson, L. and P. Goadsby (1994). Neuropeptides in migraine and cluster headache. Cephalalgia 14 (5): 320–7.
  18. Ferrari, M. and P. Saxena (1993). On serotonin and migraine: a clinical and pharmacological review. Cephalalgia 13 (3): 151–65.
  19. Goadsby, P. and L. Edvinsson (1993). Human in vivo evidence for trigeminovascular activation in cluster headache. Neuropeptide changes and effects of acute attacks therapies. Brain 117 (3): 427–34.
  20. 20.0 20.1 20.2 Durham, P (2006). Calcitonin Gene-Related Peptide (CGRP) and Migraine. Headache 48 (Suppl 1): S3–8.
  21. 21.0 21.1 Goadsby, P., L. Edvinsson, and R. Elkman (1990). Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol 28 (2): 183–7.
  22. 22.0 22.1 Edvinsson, L. (2006). Neuronal signal substances as biomarkers of migraine. Headache 46 (7): 1088–94.
  23. Lassen, L., et al. (2002). CGRP may play a causative role in migraine. Cephalalgia 22 (1): 54–61.
  24. 24.0 24.1 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 (June 2011). Keratinocyte Expression of CGRPβ: Implications for Neuropathic and Inflammatory Pain Mechanisms. Pain 152 (9): 2036–51.

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