Calcitonin gene-related peptide

calcitonin-related polypeptide alpha
Identifiers
Symbol CALCA
Alt. symbols CALC1
Entrez 796
HUGO 1437
OMIM 114130
RefSeq NM_001741
UniProt P06881
Other data
Locus Chr. 11 p15.2
calcitonin-related polypeptide, beta
Identifiers
Symbol CALCB
Alt. symbols CALC2
Entrez 797
HUGO 1438
OMIM 114160
RefSeq NM_000728
UniProt P10092
Other data
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[1] 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.[2]

Function

CGRP is produced in both peripheral and central neurons.[3] It is a potent peptide vasodilator and can function in the transmission of pain.[4][5] 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.[6] 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 through a heteromeric receptor composed of a G protein-coupled receptor called calcitonin receptor-like receptor (CALCRL) and a receptor activity-modifying protein (RAMP1).[7] 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).[8]The extracellular loop number 2 is fundamental for ligand induced activation, with key interactions of R274/Y278/D280/W283.[9]

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,[10] cytokines such as TNFα [11] and iNOS.[12]

5HT1 receptor agonists, such as sumatriptan, increase intracellular calcium, which cause decreases in CGRP promoter activity.[10] Botulinum toxin type A is able to prevent stimulated release of CGRP through the cleavage of SNAP-25 protein.[13] Receptor antagonists may also have the potential of limiting the effects of CGRP, though one promising drug candidate in this class (telcagepant) was withdrawn[14] by Merck Pharmaceuticals after phase III trials.[15]

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.[16][17][18][19][20][21] There is amounting evidence to suggest that CGRP is beneficial in preventing the development of hypertension and cardiovascular pathologies associated with hypertension.[22] Recently a study has been published investigating the protective role of alpha-CGRP in an animal model of hypertension by use of alpha-CGRP knockout mice. Here, the authors show that mice lacking alpha-CGRP gene progress to develop significantly worse hypertension, vascular fibrosis and vascular inflammation attributable to a pro-oxidant milieu.[23]

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.[24] This CGRP then binds to and activates CGRP receptors located around meningeal vessels, causing vasodilation, mast cell degranulation, and plasma extravasation.[8][24][25][26] 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.[8][24][25][26] Furthermore, intravenous administration of alpha-CGRP is able to induce headache in individuals susceptible to migraine.[27]

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.[28] 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.[28] 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.

References

  1. ↑ Amara, SG; Jonas, V; Rosenfeld, MG; Ong, ES; Evans, RM (15 July 1982). "Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products.". Nature. 298 (5871): 240–4. PMID 6283379. doi:10.1038/298240a0.
  2. ↑ 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. PMID 19062206. doi:10.1016/j.braindev.2008.10.011.
  3. ↑ 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. PMID 6346105. doi:10.1038/304129a0.
  4. ↑ Brain SD, Williams TJ, Tippins JR, Morris HR, MacIntyre I (1985). "Calcitonin gene-related peptide is a potent vasodilator". Nature. 313 (5997): 54–6. PMID 3917554. doi:10.1038/313054a0.
  5. ↑ McCulloch, J.; et al. (1986). "Calcitonin gene-related peptide: functional role in cerebrovascular regulation". Proc Natl Acad Sci USA. 83 (15): 5731–5735. PMC 386363 Freely accessible. PMID 3488550. doi:10.1073/pnas.83.15.5731.
  6. ↑ 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. PMID 19969463. doi:10.1016/j.jocn.2009.03.042.
  7. ↑ 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. PMID 12037140. doi:10.1124/pr.54.2.233.
  8. 1 2 3 Arulmani, U.; et al. (2004). "Calcitonin gene-related peptide and its role in migraine pathophysiology". Eur J Pharmacol. 500 (1–3): 315–30. PMID 15464043. doi:10.1016/j.ejphar.2004.07.035.
  9. ↑ Woolley, MJ.; Simms, J.; Mobarec, J.C.; Reynolds, C.A.; Poyner, D.; Conner, A.C.; et al. (2017). "Understanding the molecular functions of the second extracellular loop (ECL2) of the calcitonin gene-related peptide (CGRP) receptor using a comprehensive mutagenesis approach". Mol Cell Endocrinol. PMID 28572046. doi:10.1016/j.mce.2017.05.034.
  10. 1 2 Durham, P.; 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. PMID 12574409.
  11. ↑ 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. PMID 12684435.
  12. ↑ Li, J.; C. Vause; P. Durham (2008). "Calcitonin gene-related peptide stimulation of nitric oxide synthesis and release from trigeminal ganglion glial cells". Brain Research. 1196: 22–32. PMC 2268710 Freely accessible. PMID 18221935. doi:10.1016/j.brainres.2007.12.028.
  13. ↑ Durham, P.; R. Cady; 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. PMID 14979881. doi:10.1111/j.1526-4610.2004.04007.x.
  14. ↑ Merck Announces Second Quarter 2011 Financial Results
  15. ↑ Tepper, S.J.; M.J. Stillman (2008). "Clinical and preclinical rationale for CGRP-receptor antagonists in the treatment of migraine". Headache. 48 (8): 1259–68. PMID 18808506. doi:10.1111/j.1526-4610.2008.01214.x.
  16. ↑ Buzzi, M.; M. Bonamini; M. Moskowitz (1995). "Neurogenic model of migraine". Cephalalgia. 15 (4): 277–280. PMID 7585923. doi:10.1046/j.1468-2982.1995.1504277.x.
  17. ↑ Goto, K.; et al. (1992). "Calcitonin gene-related peptide in the regulation of cardiac function". Ann NY Acad Sci. 657: 194–203. PMID 1637085. doi:10.1111/j.1749-6632.1992.tb22768.x.
  18. ↑ Joyce, C.; et al. (1990). "Calcitonin gene-related peptide levels are elevated in patients with sepsis". Surgery. 108 (6): 1097–101. PMID 2247835.
  19. ↑ Edvinsson, L.; P. Goadsby (1994). "Neuropeptides in migraine and cluster headache". Cephalalgia. 14 (5): 320–7. PMID 7828188. doi:10.1046/j.1468-2982.1994.1405320.x.
  20. ↑ Ferrari, M.; P. Saxena (1993). "On serotonin and migraine: a clinical and pharmacological review". Cephalalgia. 13 (3): 151–65. PMID 8395342. doi:10.1046/j.1468-2982.1993.1303151.x.
  21. ↑ Goadsby, P.; 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. PMID 7518321. doi:10.1093/brain/117.3.427.
  22. ↑ Russell, F. A.; King, R.; Smillie, S.-J.; Kodji, X.; Brain, S. D. (2014-10-01). "Calcitonin Gene-Related Peptide: Physiology and Pathophysiology". Physiological Reviews. 94 (4): 1099–1142. ISSN 0031-9333. PMC 4187032 Freely accessible. PMID 25287861. doi:10.1152/physrev.00034.2013. Retrieved 2015-04-17.
  23. ↑ Smillie, Sarah-Jane; King, Ross; Kodji, Xenia; Outzen, Emilie; Pozsgai, Gabor; Fernandes, Elizabeth; Marshall, Nichola; Winter, Patricia de; Heads, Richard J. (05/01/2014). "An Ongoing Role of α-Calcitonin Gene–Related Peptide as Part of a Protective Network Against Hypertension, Vascular Hypertrophy, and Oxidative Stress". Hypertension. 63 (5): 1056–1062. ISSN 0194-911X. PMID 24516108. doi:10.1161/HYPERTENSIONAHA.113.02517. Retrieved 2015-04-17. Check date values in: |date= (help)
  24. 1 2 3 Durham, P (2006). "Calcitonin Gene-Related Peptide (CGRP) and Migraine". Headache. 48 (Suppl 1): S3–8. PMC 3134175 Freely accessible. PMID 16927957. doi:10.1111/j.1526-4610.2006.00483.x.
  25. 1 2 Goadsby, P.; L. Edvinsson; R. Elkman (1990). "Vasoactive peptide release in the extracerebral circulation of humans during migraine headache". Ann Neurol. 28 (2): 183–7. PMID 1699472. doi:10.1002/ana.410280213.
  26. 1 2 Edvinsson, L. (2006). "Neuronal signal substances as biomarkers of migraine". Headache. 46 (7): 1088–94. PMID 16866713. doi:10.1111/j.1526-4610.2006.00502.x.
  27. ↑ Lassen, L.; et al. (2002). "CGRP may play a causative role in migraine". Cephalalgia. 22 (1): 54–61. PMID 11993614. doi:10.1046/j.1468-2982.2002.00310.x.
  28. 1 2 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. PMC 3157543 Freely accessible. PMID 21641113. doi:10.1016/j.pain.2011.04.033.
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