Calretinin Explained

Calretinin should not be confused with calreticulin.

Calretinin, also known as calbindin 2 (formerly 29 kDa calbindin), is a calcium-binding protein involved in calcium signaling.^[1] In humans, the calretinin protein is encoded by the CALB2 gene.^{[2] [3]}

Function

This gene encodes an intracellular calcium-binding protein belonging to the troponin C superfamily. Members of this protein family have six EF-hand domains which bind calcium. This protein plays a role in diverse cellular functions, including message targeting and intracellular calcium buffering.^[2]

Calretinin is abundantly expressed in neurons including retina (which gave it the name)^[1] and cortical interneurons.^[4] Expression was found in different neurons than that of the similar vitamin D-dependent calcium-binding protein, calbindin-28kDa.^[1]

Calretinin has an important role as a modulator of neuronal excitability including the induction of long-term potentiation.^[5] Loss of expression of calretinin in hippocampal interneurons has been suggested to be relevant in temporal lobe epilepsy.^[6]

It is expressed in a number of other locations including hair follicles.^[7]

Clinical significance

Calretinin is a diagnostic marker for some human diseases, including Hirschsprung disease and some cancers.

Mesothelioma

Using immunohistochemistry, calretinin can be demonstrated in both benign mesothelium and in malignant mesothelioma^{[8] [9]} and can be used to help differentiate different lung tumours.^[10] Antibodies to calretinin can also be used to distinguish between different types of brain tumour, demonstrating only those with neuronal rather than glial, differentiation.^[11] Furthermore, the essential function of calretinin in mesothelioma cell lines has been demonstrated in vitro and may be an interesting target for therapeutical approaches.^[12]

Hirschsprung disease

In Hirschsprung disease, calretinin immunohistochemistry offers additional diagnostic value in specimens with inadequate amount of submucosa and rarely seen ganglion cells. The presence of ganglion cells consistently correlated with calretinin-positive thin nerve fibrils in the lamina propria, muscularis mucosae and superficial submucosa. These calretinin-positive thin neurofibrils are absent in the aganglionic segments of bowel and in the areas without ganglion cells from the junction of normal with diseased rectum. Calretinin is strongly expressed in the submucosal and subserosal nerve trunks in the ganglionic segment. No calretinin expression is seen in the nerve trunks in the rest of the aganglionic segment. It has faint expression in the thick nerve trunks from the areas without ganglion cells. Faint positivity of the thick submucosal and subserosal nerves in the absence of ganglion cells and calretinin positive nerve fibrils, is characteristic of the junction of the aganglionic-to-normal rectum.^[13]

Further reading

• Alaeddini M, Etemad-Moghadam S, Baghaii F . Comparative expression of calretinin in selected odontogenic tumours: a possible relationship to histogenesis . Histopathology . 52 . 3 . 299–304 . Feb 2008 . 18269580 . 10.1111/j.1365-2559.2007.02948.x . 205299356 .
• Guinard-Samuel V, Bonnard A, De Lagausie P, Philippe-Chomette P, Alberti C, El Ghoneimi A, Peuchmaur M, Berrebi-Binczak D . Calretinin immunohistochemistry: a simple and efficient tool to diagnose Hirschsprung disease . Modern Pathology . 22 . 10 . 1379–84 . Oct 2009 . 19648883 . 10.1038/modpathol.2009.110 . 643637 . free .
• Seress L, Abrahám H, Czéh B, Fuchs E, Léránth C . Calretinin expression in hilar mossy cells of the hippocampal dentate gyrus of nonhuman primates and humans . Hippocampus . 18 . 4 . 425–34 . 2008 . 18189312 . 10.1002/hipo.20403 . 36785826 .
• Zhang H, Bu H, Chen H, Wei B, Liu W, Guo J, Li F, Liao D, Tang Y, Zhang Z . Comparison of immunohistochemical markers in the differential diagnosis of adrenocortical tumors: immunohistochemical analysis of adrenocortical tumors . Applied Immunohistochemistry & Molecular Morphology . 16 . 1 . 32–9 . Jan 2008 . 18091323 . 10.1097/PAI.0b013e318032cf56 . 10136695 .
• Vonlanthen S, Kawecki TJ, Betticher DC, Pfefferli M, Schwaller B . Heterozygosity of SNP513 in intron 9 of the human calretinin gene (CALB2) is a risk factor for colon cancer . Anticancer Research . 27 . 6C . 4279–88 . 2007 . 18214032 .
• Barbe L, Lundberg E, Oksvold P, Stenius A, Lewin E, Björling E, Asplund A, Pontén F, Brismar H, Uhlén M, Andersson-Svahn H . Toward a confocal subcellular atlas of the human proteome . Molecular & Cellular Proteomics . 7 . 3 . 499–508 . Mar 2008 . 18029348 . 10.1074/mcp.M700325-MCP200 . 10810250 . free .
• Lee ES, Leong AS, Kim YS, Lee JH, Kim I, Ahn GH, Kim HS, Chun YK . Calretinin, CD34, and alpha-smooth muscle actin in the identification of peritoneal invasive implants of serous borderline tumors of the ovary . Modern Pathology . 19 . 3 . 364–72 . Mar 2006 . 16415795 . 10.1038/modpathol.3800539 . 12266907 . free .
• Iio K, Nagasawa Y, Iwatani H, Yamamoto R, Horii A, Okuzaki D, Furumatsu Y, Inohara H, Nojima H, Imai E, Isaka Y, Rakugi H . Microarray analysis of tonsils in immunoglobulin A nephropathy patients . Biochemical and Biophysical Research Communications . 393 . 4 . 565–70 . Mar 2010 . 20138841 . 10.1016/j.bbrc.2010.01.120 .
• DeVilliers P, Liu H, Suggs C, Simmons D, Daly B, Zhang S, Raubenheimer E, Larsson A, Wright T . Calretinin expression in the differential diagnosis of human ameloblastoma and keratocystic odontogenic tumor . The American Journal of Surgical Pathology . 32 . 2 . 256–60 . Feb 2008 . 18223328 . 10.1097/PAS.0b013e3181452176 . 19045101 .
• Portugal R, Oliva E . Calretinin: diagnostic utility in the female genital tract . Advances in Anatomic Pathology . 16 . 2 . 118–24 . Mar 2009 . 19550372 . 10.1097/PAP.0b013e31819923ce . 22438395 .
• Winn B, Tavares R, Fanion J, Noble L, Gao J, Sabo E, Resnick MB . Differentiating the undifferentiated: immunohistochemical profile of medullary carcinoma of the colon with an emphasis on intestinal differentiation . Human Pathology . 40 . 3 . 398–404 . Mar 2009 . 18992917 . 2657293 . 10.1016/j.humpath.2008.08.014 .
• Melotti A, Daga A, Marubbi D, Zunino A, Mutti L, Corte G . In vitro and in vivo characterization of highly purified human mesothelioma derived cells . BMC Cancer . 10 . 54 . 2010 . 20175889 . 2850899 . 10.1186/1471-2407-10-54 . free .
• Häner K, Henzi T, Pfefferli M, Künzli E, Salicio V, Schwaller B . A bipartite butyrate-responsive element in the human calretinin (CALB2) promoter acts as a repressor in colon carcinoma cells but not in mesothelioma cells . Journal of Cellular Biochemistry . 109 . 3 . 519–31 . Feb 2010 . 19998412 . 10.1002/jcb.22429 . 206017499 .
• Henzi T, Blum WV, Pfefferli M, Kawecki TJ, Salicio V, Schwaller B . SV40-induced expression of calretinin protects mesothelial cells from asbestos cytotoxicity and may be a key factor contributing to mesothelioma pathogenesis . The American Journal of Pathology . 174 . 6 . 2324–36 . Jun 2009 . 19435792 . 2684196 . 10.2353/ajpath.2009.080352 .
• Barinka F, Druga R, Marusic P, Krsek P, Zamecnik J . Calretinin immunoreactivity in focal cortical dysplasias and in non-malformed epileptic cortex . Epilepsy Research . 88 . 1 . 76–86 . Jan 2010 . 19854615 . 10.1016/j.eplepsyres.2009.09.021 . 22595044 .
• Mai KT, Teo I, Al Moghrabi H, Marginean EC, Veinot JP . Calretinin and CD34 immunoreactivity of the endometrial stroma in normal endometrium and change of the immunoreactivity in dysfunctional uterine bleeding with evidence of 'disordered endometrial stroma' . Pathology . 40 . 5 . 493–9 . Aug 2008 . 18604736 . 10.1080/00313020802197897 . 24627207 .
• Massouh M, Wallman MJ, Pourcher E, Parent A . The fate of the large striatal interneurons expressing calretinin in Huntington's disease . Neuroscience Research . 62 . 4 . 216–24 . Dec 2008 . 18801393 . 10.1016/j.neures.2008.08.007 . 23242064 .
• Rougemont AL, Sartelet H, Oligny LL, Bensoussan A, Yazbeck S, Fournet JC . Accessory liver lobe with mesothelial inclusion cysts in an omphalocele: a new malformative association . Pediatric and Developmental Pathology . 10 . 3 . 224–8 . 2007 . 17535091 . 10.2350/06-08-0148.1 . 41971082 .
• Clements RJ, McDonough J, Freeman EJ . Distribution of parvalbumin and calretinin immunoreactive interneurons in motor cortex from multiple sclerosis post-mortem tissue . Experimental Brain Research . 187 . 3 . 459–65 . May 2008 . 18297277 . 10.1007/s00221-008-1317-9 . 18256420 .

Notes and References

1. Rogers JH. Calretinin: a gene for a novel calcium-binding protein expressed principally in neurons. . J Cell Biol . 1987 . 105 . 3 . 1343–53 . 3654755 . 10.1083/jcb.105.3.1343. 2114790 .
2. Web site: Entrez Gene: calbindin 2.
3. Parmentier M, Passage E, Vassart G, Mattei MG . The human calbindin D28k (CALB1) and calretinin (CALB2) genes are located at 8q21.3----q22.1 and 16q22----q23, respectively, suggesting a common duplication with the carbonic anhydrase isozyme loci . Cytogenetics and Cell Genetics . 57 . 1 . 41–3 . 1991 . 1906795 . 10.1159/000133111 .
4. Barinka F, Druga R. Calretinin expression in the mammalian neocortex: a review. . Physiol Res . 2010 . 59 . 5 . 665–77 . 10.33549/physiolres.931930 . 20406030 . free .
5. Camp AJ, Wijesinghe R. Calretinin: modulator of neuronal excitability. . Int J Biochem Cell Biol . 2009 . 41 . 11 . 2118–21 . 19450707 . 10.1016/j.biocel.2009.05.007 .
6. Tóth K, Maglóczky Z. The vulnerability of calretinin-containing hippocampal interneurons to temporal lobe epilepsy. . Front Neuroanat . 2014 . 8 . 100 . 25324731 . 10.3389/fnana.2014.00100 . 4179514 . free .
7. Poblet E, Jimenez F, de Cabo C, Prieto-Martin A, Sánchez-Prieto R . The calcium-binding protein calretinin is a marker of the companion cell layer of the human hair follicle . The British Journal of Dermatology . 152 . 6 . 1316–20 . Jun 2005 . 15948999 . 10.1111/j.1365-2133.2005.06603.x . 23551756 .
8. Saydan N, Salicio V, Cappelli-Gotzos B, Gotzos V . Expression of calretinin in human mesothelioma cell lines and cell cycle analysis by flow cytometry . Anticancer Research . 21 . 1A . 181–8 . 2001 . 11299732 .
9. Gotzos. V.. Vogt. P.. Celio. M. R.. 1996-02-01. The calcium binding protein calretinin is a selective marker for malignant pleural mesotheliomas of the epithelial type. Pathology, Research and Practice. 192. 2. 137–147. 10.1016/S0344-0338(96)80208-1. 0344-0338. 8692714.
10. Marchevsky AM . Application of immunohistochemistry to the diagnosis of malignant mesothelioma . Archives of Pathology & Laboratory Medicine . 132 . 3 . 397–401 . Mar 2008 . 18318582 . 10.5858/2008-132-397-AOITTD .
11. Book: Leong, Anthony S-Y. Cooper, Kumarason. Leong, F Joel W-M. 2003. Manual of Diagnostic Cytology. 2. Greenwich Medical Media, Ltd.. 45–46. 978-1-84110-100-2.
12. Blum. Walter. Schwaller. Beat. 2013-11-01. Calretinin is essential for mesothelioma cell growth/survival in vitro: a potential new target for malignant mesothelioma therapy?. International Journal of Cancer. 133. 9. 2077–2088. 10.1002/ijc.28218. 1097-0215. 23595591. 25380668.
13. Alexandrescu S, Rosenberg H, Tatevian N . Role of calretinin immunohistochemical stain in evaluation of Hirschsprung disease: an institutional experience . International Journal of Clinical and Experimental Pathology . 6 . 12 . 2955–61 . 2013 . 24294384 . 3843278 .