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Gene Review

CALCA  -  calcitonin-related polypeptide alpha

Homo sapiens

Synonyms: CALC1, CGRP, CGRP-I, CGRP1, CT, ...
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Disease relevance of CALCA


Psychiatry related information on CALCA

  • Ethanol-induced release of CGRP may contribute to the reduction in the risk of CAD associated with alcohol consumption by various mechanisms, including the increase in coronary flow and arterial dilatation [6].
  • Thus, it is thought that both CT and A beta, which are formed during the processing of APP, may participate in the neuronal degeneration in Alzheimer's disease by different mechanisms [7].
  • Thus upregulation of CGRP mRNA and iCGRP levels are temporally related to the development of inflammation and lowered pain thresholds [8].
  • In a rat model of tendon rupture using semiquantitative methodology, healing was assessed according to the diameter of newly organized collagen and the occurrence of the sensory neuropeptides (SP, CGRP) in relation to different levels of physical activity [9].
  • Conversely, in the hot-plate test CGRP was effective in enhancing response latencies only at the highest dose of 10 micrograms/rat, while sCT (0.125, 0.25 and 2.5 micrograms/rat) inhibited the hot-plate response dose-dependently [10].

High impact information on CALCA

  • This review summarizes the receptor-mediated vascular activities of calcitonin gene-related peptide (CGRP) and the structurally related peptide adrenomedullin (AM) [3].
  • Evidence for the selective activity of the first nonpeptide CGRP antagonist BIBN4096BS for the CGRP receptor is presented [3].
  • CGRP is a 37-amino acid neuropeptide, primarily released from sensory nerves, whilst AM is produced by stimulated vascular cells, and amylin is secreted from the pancreas [3].
  • The calcitonin/CGRP gene is a complex transcription unit in which developmentally regulated cell-specific alternative RNA processing results in the production of CGRP mRNA in neurons, and of calcitonin mRNA in thyroid C cells [11].
  • Splice commitment dictates neuron-specific alternative RNA processing in calcitonin/CGRP gene expression [11].

Chemical compound and disease context of CALCA

  • Since it has recently been shown that human CGRP (hCGRP) lowers plasma calcium levels in both the rat and the rabbit, we examined the in vitro effects of human synthetic CGRP on bone resorption (as measured by 45Ca release) stimulated by PTH, prostaglandin E2, and 1,25-dihydroxyvitamin D3 [12].
  • CGRP (10(-6)-10(-8) M) also inhibited resorption stimulated by prostaglandin and 1,25-dihydroxyvitamin D3 in a dose-dependent manner, but had no significant effect on basal bone resorption [12].
  • Structure-activity relationships for the binding of human alpha-calcitonin gene-related peptide 8-37 (halphaCGRP8-37) have been investigated at the CGRP receptors expressed by human SK-N-MC (neuroblastoma) and Col 29 (colonic epithelia) cells by radioligand binding assays and functional assays (halphaCGRP stimulation of adenylate cyclase) [13].
  • We conclude that WE-68 Ewing's sarcoma cells express genuine CGRP receptors which upon activation lead to stimulation of cyclic AMP formation[14]
  • In Xenopus oocytes with an endogenous calcitonin gene-related peptide (CGRP) receptor, a receptor activity modifying protein (RAMP1) enhancing CGRP stimulated chloride currents of the cystic fibrosis transmembrane regulator was recently cloned [McLatchie, L.M. et al. (1998) Nature 393, 333-339] [15].

Biological context of CALCA

  • This chromosome segment includes the genes for insulin-like growth factor 2, beta-hemoglobin, calcitonin A (CALCA), and parathyroid hormone (PTH) [16].
  • Women with any CALCA C allele were at nonsignificantly higher risk of ovarian cancer (OR: 1.5, 95% CI: 0.9-2.3) compared to women with the TT genotype and the risk increased with the number of C alleles (P for trend: 0.05) [1].
  • Data from a population-based case-control study conducted in Hawaii were used to examine the hypothesis that a T --> C transition 624 base pairs upstream (-624) of the translation initiation codon of the CALCA gene influences the risk of ovarian malignancy [1].
  • Considering the patients with central nervous system (CNS) infiltration, the estimated 2-year overall survival (OS) was 20% for those with methylation in CALCA promoter and 85% for those without (p=0.001) [2].
  • These results suggest that mitotic deletion mapping may be as useful as meiotic deletion or recombination mapping in ordering closely linked markers, such as CALCA and PTH, for which other approaches, including physical mapping and multipoint linkage analysis, have failed to accurately identify the gene order [17].

Anatomical context of CALCA

  • DNA extracts from normal leukocytes and 48 tumor samples were analyzed by Southern blotting using the polymorphic probes pEJ6.6 (HRAS1), phins310 (INS), p20.36 (PTH), and pEM36 (CALCA) [18].
  • We now report that human pancreatic amylin and rat CGRP-1 are potent inhibitors of both basal and insulin-stimulated rates of glycogen synthesis in stripped rat soleus muscle in vitro [19].
  • Transfection of this cDNA into COS cells resulted in expression of receptors with high affinity for salmon CT (Kd = approximately 0.44 nM) and for human CT (Kd = approximately 5.4 nM) [20].
  • In conclusion, CGRP II, unlike CGRP I, inhibits gastric acid secretion in humans [21].
  • The amino acid sequence of CGRP-I was obtained in medullary thyroid carcinoma extracts (Morris, H. R., Panico, M., Etienne, T., Tippins, J., Girgis, S. I., and MacIntyre, I. (1984) Nature 308, 746-748), but not in normal human tissues [22].

Associations of CALCA with chemical compounds


Physical interactions of CALCA

  • CGRP binding and receptor activation lead to the phosphorylation of CRLR and the internalization of the receptor as a stable complex [26].
  • The anatomical distribution and the pharmacological characteristics of amylin binding sites in the rat brain are different from those reported for CGRP but share several similarities with the salmon calcitonin receptors [27].
  • Coupling of hADM binding to cAMP stimulation is less efficient than for hCGRP-I and is reduced by deletion of the unique 12 amino acid sequence of hADM N-terminal to the ring structure [28].
  • Because neutrophil infiltration of the clear corneal surface is a hallmark of corneal inflammation in the human eye, we determined whether CGRP can bind to human corneal epithelial cells (HCEC) and induce expression of the neutrophil chemotactic protein IL-8 [29].
  • These studies suggest that CGRP initially interacts with the calcitonin receptor to produce a calcitonin-like effect, which is followed by hypercalcaemia presumably by antagonising the action of endogenous circulating calcitonin [30].

Regulatory relationships of CALCA

  • The binding of CGRP and its ability to stimulate cAMP production were investigated in mutant and wild-type receptors after transient transfection into COS-7 cells with RAMP1 [31].
  • Furthermore, CGRP-induced relaxation of placental vessels are inhibited by a CGRP receptor antagonist (CGRP8-37), ATP-sensitive potassium (KATP) channel blocker (glybenclamide), and cAMP-dependent protein kinase A inhibitor (Rp-cAMPS) and partially inhibited by a nitric oxide inhibitor (Nomega-nitro-l-arginine methyl ester) [32].
  • We found that CGRP-expressing fibers in the pancreatic islets also express TRPV1 [33].
  • In conclusion, both CGRP and adrenomedullin induced vasodilation via CGRP receptors in human lenticulostriate artery of various diameter [34].
  • We conclude that, in addition to the previously characterized direct smooth muscle relaxant action via CGRP1 receptors (Maggi et al. Regulatory Peptides 61, 27-36, 1996), CGRP also induces a remarkable potentiation of excitatory neurotransmission to the circular muscle of the guinea-pig colon via CGRP2 receptors [35].

Other interactions of CALCA

  • Although the calcitonin receptor does not require RAMP to bind and respond to calcitonin, it can associate with the RAMPs, resulting in a series of receptors that typically have high affinity for amylin and varied affinity for CGRP [36].
  • A non-BWS translocation breakpoint was more proximal, between HBB and calcitonin-A (CALCA) [37].
  • In addition, human alpha-CGRP (8-37) is an effective antagonist of the hemodynamic actions of rat IAPP [38].
  • Interestingly, the L94A mutant up-regulated surface expression of the receptor heterodimer to a greater degree than wild-type hRAMP1, thereby increasing CGRP binding and signaling [39].
  • Our data suggest that the neuroendocrine peptides VIP, CGRP, and CT may exert functional roles during MG and malignant transformation of the human thymus [40].

Analytical, diagnostic and therapeutic context of CALCA

  • The present study was undertaken to compare in healthy volunteers the effects of intravenous infusions of CGRP I and CGRP II (79 pmol/kg.h) on pentagastrin-stimulated acid secretion to those of calcitonin (88 pmol/kg.h) [21].
  • CGRP expression was confirmed in cultured decidual cells by Southern blot analysis and immunocytochemistry and by RIA in culture medium [41].
  • After total thyroidectomy, the samples were examined for CT, chromogranin A, and SSTR expression by RT-PCR [42].
  • The CGRP dose-dependently increased (up to 50-fold) cAMP formation in cell cultures, an effect significantly blocked by 0.1 to 10 micromol/L of the CGRP1 receptor antagonist CGRP8-37 [5].
  • 3. In experiments measuring changes in local blood flow in rat skin by a 133xenon clearance technique, intradermal injection of both ADM13-52 (3-300 pmol) and CGRP (0.1-30 pmol) evoked dose-related increases in local blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)[43]


  1. Calcitonin gene polymorphism CALCA-624 (T/C) and ovarian cancer. Goodman, M.T., Ferrell, R., McDuffie, K., Thompson, P.J., Wilkens, L.R., Bushley, A.W., Tung, K.H., Carney, M.E., Ness, R.B. Environ. Mol. Mutagen. (2005) [Pubmed]
  2. Hypermethylation of CpG island in the promoter region of CALCA in acute lymphoblastic leukemia with central nervous system (CNS) infiltration correlates with poorer prognosis. Paixão, V.A., Vidal, D.O., Caballero, O.L., Vettore, A.L., Tone, L.G., Ribeiro, K.B., Lopes, L.F. Leuk. Res. (2006) [Pubmed]
  3. Vascular actions of calcitonin gene-related peptide and adrenomedullin. Brain, S.D., Grant, A.D. Physiol. Rev. (2004) [Pubmed]
  4. Amylin, calcitonin gene-related peptide, calcitonin, and adrenomedullin: a peptide superfamily. Wimalawansa, S.J. Critical reviews in neurobiology. (1997) [Pubmed]
  5. Functional calcitonin gene-related peptide type 1 and adrenomedullin receptors in human trigeminal ganglia, brain vessels, and cerebromicrovascular or astroglial cells in culture. Moreno, M.J., Cohen, Z., Stanimirovic, D.B., Hamel, E. J. Cereb. Blood Flow Metab. (1999) [Pubmed]
  6. Ethanol dilates coronary arteries and increases coronary flow via transient receptor potential vanilloid 1 and calcitonin gene-related peptide. Gazzieri, D., Trevisani, M., Tarantini, F., Bechi, P., Masotti, G., Gensini, G.F., Castellani, S., Marchionni, N., Geppetti, P., Harrison, S. Cardiovasc. Res. (2006) [Pubmed]
  7. Neurotoxicity of a carboxyl-terminal fragment of the Alzheimer's amyloid precursor protein. Kim, S.H., Suh, Y.H. J. Neurochem. (1996) [Pubmed]
  8. Muscle inflammation induces a rapid increase in calcitonin gene-related peptide (CGRP) mRNA that temporally relates to CGRP immunoreactivity and nociceptive behavior. Ambalavanar, R., Dessem, D., Moutanni, A., Yallampalli, C., Yallampalli, U., Gangula, P., Bai, G. Neuroscience (2006) [Pubmed]
  9. Physical activity modulates nerve plasticity and stimulates repair after achilles tendon rupture. Bring, D.K., Kreicbergs, A., Renstrom, P.A., Ackermann, P.W. J. Orthop. Res. (2007) [Pubmed]
  10. Calcitonin gene-related peptide: antinociceptive activity in rats, comparison with calcitonin. Pecile, A., Guidobono, F., Netti, C., Sibilia, V., Biella, G., Braga, P.C. Regul. Pept. (1987) [Pubmed]
  11. Splice commitment dictates neuron-specific alternative RNA processing in calcitonin/CGRP gene expression. Leff, S.E., Evans, R.M., Rosenfeld, M.G. Cell (1987) [Pubmed]
  12. Human synthetic calcitonin gene-related peptide inhibits bone resorption in vitro. D'Souza, S.M., MacIntyre, I., Girgis, S.I., Mundy, G.R. Endocrinology (1986) [Pubmed]
  13. Structural determinants for binding to CGRP receptors expressed by human SK-N-MC and Col 29 cells: studies with chimeric and other peptides. Poyner, D.R., Soomets, U., Howitt, S.G., Langel, U. Br. J. Pharmacol. (1998) [Pubmed]
  14. Functional characteristics of calcitonin gene-related peptide receptors in human Ewing's sarcoma WE-68 cells. van Valen, F., Keck, E., Jürgens, H. FEBS Lett. (1989) [Pubmed]
  15. Receptor activity modifying proteins regulate the activity of a calcitonin gene-related peptide receptor in rabbit aortic endothelial cells. Muff, R., Leuthäuser, K., Bühlmann, N., Foord, S.M., Fischer, J.A., Born, W. FEBS Lett. (1998) [Pubmed]
  16. Molecular characterization of Beckwith-Wiedemann syndrome (BWS) patients with partial duplication of chromosome 11p excludes the gene MYOD1 from the BWS region. Weksberg, R., Glaves, M., Teshima, I., Waziri, M., Patil, S., Williams, B.R. Genomics (1990) [Pubmed]
  17. Mitotic deletions of 11p15.5 in two different tumors indicate that the CALCA locus is distal to the PTH locus. Henry, I., Grandjouan, S., Barichard, F., Huerre-Jeanpierre, C., Junien, C. Cytogenet. Cell Genet. (1989) [Pubmed]
  18. Loss of constitutional heterozygosity on chromosome 11p in human ovarian cancer. Positive correlation with grade of differentiation. Kiechle-Schwarz, M., Bauknecht, T., Wienker, T., Walz, L., Pfleiderer, A. Cancer (1993) [Pubmed]
  19. Pancreatic amylin and calcitonin gene-related peptide cause resistance to insulin in skeletal muscle in vitro. Leighton, B., Cooper, G.J. Nature (1988) [Pubmed]
  20. Cloning, characterization, and expression of a human calcitonin receptor from an ovarian carcinoma cell line. Gorn, A.H., Lin, H.Y., Yamin, M., Auron, P.E., Flannery, M.R., Tapp, D.R., Manning, C.A., Lodish, H.F., Krane, S.M., Goldring, S.R. J. Clin. Invest. (1992) [Pubmed]
  21. Calcitonin gene-related peptides I and II and calcitonin: distinct effects on gastric acid secretion in humans. Beglinger, C., Born, W., Hildebrand, P., Ensinck, J.W., Burkhardt, F., Fischer, J.A., Gyr, K. Gastroenterology (1988) [Pubmed]
  22. Identification in the human central nervous system, pituitary, and thyroid of a novel calcitonin gene-related peptide, and partial amino acid sequence in the spinal cord. Petermann, J.B., Born, W., Chang, J.Y., Fischer, J.A. J. Biol. Chem. (1987) [Pubmed]
  23. The second intracellular loop of the calcitonin gene-related peptide receptor provides molecular determinants for signal transduction and cell surface expression. Conner, A.C., Simms, J., Howitt, S.G., Wheatley, M., Poyner, D.R. J. Biol. Chem. (2006) [Pubmed]
  24. Proadrenomedullin-derived peptides in the paracrine control of the hypothalamo-pituitary-adrenal axis. Nussdorfer, G.G. Int. Rev. Cytol. (2001) [Pubmed]
  25. Calcitonin gene-related peptide relates to cough sensitivity in children with chronic cough. Chang, A.B., Gibson, P.G., Ardill, J., McGarvey, L.P. Eur. Respir. J. (2007) [Pubmed]
  26. Agonist-promoted internalization of a ternary complex between calcitonin receptor-like receptor, receptor activity-modifying protein 1 (RAMP1), and beta-arrestin. Hilairet, S., Bélanger, C., Bertrand, J., Laperrière, A., Foord, S.M., Bouvier, M. J. Biol. Chem. (2001) [Pubmed]
  27. Neuroanatomical localization, pharmacological characterization and functions of CGRP, related peptides and their receptors. van Rossum, D., Hanisch, U.K., Quirion, R. Neuroscience and biobehavioral reviews. (1997) [Pubmed]
  28. Adrenomedullin and calcitonin gene-related peptide interact with the same receptor in cultured human neuroblastoma SK-N-MC cells. Zimmermann, U., Fischer, J.A., Muff, R. Peptides (1995) [Pubmed]
  29. Calcitonin gene-related peptide induces IL-8 synthesis in human corneal epithelial cells. Tran, M.T., Ritchie, M.H., Lausch, R.N., Oakes, J.E. J. Immunol. (2000) [Pubmed]
  30. A dual effect of calcitonin gene-related peptide on plasma calcium levels in the chick. Bevis, P.J., Zaidi, M., MacIntyre, I. Biochem. Biophys. Res. Commun. (1990) [Pubmed]
  31. A key role for transmembrane prolines in calcitonin receptor-like receptor agonist binding and signalling: implications for family B G-protein-coupled receptors. Conner, A.C., Hay, D.L., Simms, J., Howitt, S.G., Schindler, M., Smith, D.M., Wheatley, M., Poyner, D.R. Mol. Pharmacol. (2005) [Pubmed]
  32. Involvement of calcitonin gene-related peptide in control of human fetoplacental vascular tone. Dong, Y.L., Vegiraju, S., Chauhan, M., Gangula, P.R., Hankins, G.D., Goodrum, L., Yallampalli, C. Am. J. Physiol. Heart Circ. Physiol. (2004) [Pubmed]
  33. Capsaicin-sensitive sensory fibers in the islets of Langerhans contribute to defective insulin secretion in Zucker diabetic rat, an animal model for some aspects of human type 2 diabetes. Gram, D.X., Ahrén, B., Nagy, I., Olsen, U.B., Brand, C.L., Sundler, F., Tabanera, R., Svendsen, O., Carr, R.D., Santha, P., Wierup, N., Hansen, A.J. Eur. J. Neurosci. (2007) [Pubmed]
  34. CGRP and adrenomedullin receptor populations in human cerebral arteries: in vitro pharmacological and molecular investigations in different artery sizes. Sams, A., Knyihár-Csillik, E., Engberg, J., Szok, D., Tajti, J., Bodi, I., Edvinsson, L., Vécsei, L., Jansen-Olesen, I. Eur. J. Pharmacol. (2000) [Pubmed]
  35. CGRP potentiates excitatory transmission to the circular muscle of guinea-pig colon. Maggi, C.A., Giuliani, S., Santicioli, P. Regul. Pept. (1997) [Pubmed]
  36. International Union of Pharmacology. XXXII. The mammalian calcitonin gene-related peptides, adrenomedullin, amylin, and calcitonin receptors. Poyner, D.R., Sexton, P.M., Marshall, I., Smith, D.M., Quirion, R., Born, W., Muff, R., Fischer, J.A., Foord, S.M. Pharmacol. Rev. (2002) [Pubmed]
  37. Molecular characterization of cytogenetic alterations associated with the Beckwith-Wiedemann syndrome (BWS) phenotype refines the localization and suggests the gene for BWS is imprinted. Weksberg, R., Teshima, I., Williams, B.R., Greenberg, C.R., Pueschel, S.M., Chernos, J.E., Fowlow, S.B., Hoyme, E., Anderson, I.J., Whiteman, D.A. Hum. Mol. Genet. (1993) [Pubmed]
  38. Antagonistic effect of human alpha-calcitonin gene-related peptide (8-37) on regional hemodynamic actions of rat islet amyloid polypeptide in conscious Long-Evans rats. Gardiner, S.M., Compton, A.M., Kemp, P.A., Bennett, T., Bose, C., Foulkes, R., Hughes, B. Diabetes (1991) [Pubmed]
  39. Identification of the human receptor activity-modifying protein 1 domains responsible for agonist binding specificity. Kuwasako, K., Kitamura, K., Nagoshi, Y., Cao, Y.N., Eto, T. J. Biol. Chem. (2003) [Pubmed]
  40. Functional expression of receptors for calcitonin gene-related peptide, calcitonin, and vasoactive intestinal peptide in the human thymus and thymomas from myasthenia gravis patients. Marie, J., Wakkach, A., Coudray, A., Chastre, E., Berrih-Aknin, S., Gespach, C. J. Immunol. (1999) [Pubmed]
  41. Calcitonin gene-related peptide (CGRP) and CGRP receptor expression at the human implantation site. Tsatsaris, V., Tarrade, A., Merviel, P., Garel, J.M., Segond, N., Jullienne, A., Evain-Brion, D. J. Clin. Endocrinol. Metab. (2002) [Pubmed]
  42. Selective activation of somatostatin receptor subtypes differentially modulates secretion and viability in human medullary thyroid carcinoma primary cultures: potential clinical perspectives. Zatelli, M.C., Piccin, D., Tagliati, F., Bottoni, A., Luchin, A., Vignali, C., Margutti, A., Bondanelli, M., Pansini, G.C., Pelizzo, M.R., Culler, M.D., Degli Uberti, E.C. J. Clin. Endocrinol. Metab. (2006) [Pubmed]
  43. Interaction of human adrenomedullin 13-52 with calcitonin gene-related peptide receptors in the microvasculature of the rat and hamster. Hall, J.M., Siney, L., Lippton, H., Hyman, A., Kang-Chang, J., Brain, S.D. Br. J. Pharmacol. (1995) [Pubmed]
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