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Calreticulin, Cardiac Development and Congenital Complete Heart Block in Children

  • Chapter
Signal Transduction and Cardiac Hypertrophy

Part of the book series: Progress in Experimental Cardiology ((PREC,volume 7))

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Summary

Calreticulin is a Ca2+ binding chaperone resident in the lumen of endoplasmic reticulum. The protein is highly expressed in developing heart and down-regulated after birth. In mice, calreticulin deficiency is lethal due to impaired cardiac development. Over-expression of calreticulin in developing and postnatal heart leads to bradycardia, complete heart block and sudden death. This indicates that calreticulin plays an important role in the development of the cardiac conduction system and in the pathology of congential heart block. These findings may have important implications on the molecular understanding of congenital heart block and may prove to be a target for future therapies.

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References

  1. Morquio L. 1901. Sur une maladie infantile et familial characterisee par des modifications permanents du pouls des attaques syncopales et epileptiforms et la mort subite. Arch Med Inf 4:467–469.

    Google Scholar 

  2. Michaelsson M, Riesenfeld T, Jonzon A. 1997. Natural history of congenital complete atrioventricular block. Pacing Clin Electrophysiol 20:2098–2101.

    Article  PubMed  CAS  Google Scholar 

  3. Moak JP, Barron KS, Hougen TJ, Wiles HB, Balaji S, Sreeram N, Cohen MH, Nordenberg A, Van Hare GF, Friedman RA, Perez M, Cecchin F, Schneider DS, Nehgme RA, Buyon JP. 2001. Congenital heart block: development of late-onset cardiomyopathy, a previously underappreciated sequela. J Am Coll Cardiol 37:238–242.

    Article  PubMed  CAS  Google Scholar 

  4. McCue CM, Mantakas ME, Tingelstad JB, Ruddy S. 1977. Congenital heart block in newborns of mothers with connective tissue disease. Circulation 56:82–90.

    Article  PubMed  CAS  Google Scholar 

  5. Scott JS, Maddison PJ, Taylor PV, Esscher E, Scott O, Skinner RR 1983. Connective-tissue disease, antibodies to ribonucleoprotein, and congenital heart block. N Engl J Med 309:209–212.

    Article  PubMed  CAS  Google Scholar 

  6. Qu Y, Xiao GQ, Chen L, Boutjdir M. 2001. Autoantibodies from mothers of children with congenital heart block downregulate cardiac L-type Ca2+ channels. J Mol Cell Cardiol 33:1153–1163.

    Article  PubMed  CAS  Google Scholar 

  7. Boutjdir M. 2000. Molecular and ionic basis of congenital complete heart block. Trends Cardiovasc Med 10:114–122.

    Article  PubMed  CAS  Google Scholar 

  8. Frohn-Mulder IM, Meilof JF, Szatmari A, Stewart PA, Swaak TJ, Hess J. 1994. Clinical significance of maternal anti-Ro/SS-A antibodies in children with isolated heart block. J Am Coll Cardiol 23:1677–1681.

    Article  PubMed  CAS  Google Scholar 

  9. Nakamura K, Robertson M, Liu G, Dickie P, Guo JQ, Duff HJ, Opas M, Kavanagh K, Michalak M. 2001. Complete heart block and sudden death in mouse over-expressing calreticulin. J Clin Invest 107:1245–1253.

    Article  PubMed  CAS  Google Scholar 

  10. Michalak M, Corbett EF, Mesaeli N, Nakamura K, Opas M. 1999. Calreticulin: one protein, one gene, many functions. Biochem J 344:281–292.

    Article  PubMed  CAS  Google Scholar 

  11. Bergeron JJM, Brenner MB, Thomas DY, Williams DB. 1994. Calnexin: a membrane-bound chaperone of the endoplasmic reticulum. Trends Biochem Sei 19:124–128.

    Article  CAS  Google Scholar 

  12. Helenius A, Trombetta ES, Hebert DN, Simons JF. 1997. Calnexin, calreticulin and the folding of glycoproteins. Trends Cell Biol 7:193–200.

    Article  CAS  Google Scholar 

  13. Nakamura K, Zuppini A, Arnaudeau S, Lynch J, Ahsan I, Krause R, Papps S, De Smedt H, Parys, JB, Müller-Esterl W, Lew DP, Krause K-H, Demaurex N, Opas M, Michalak M. 2001. Functional specialization of calreticulin domains. J Cell Biol 154:961–972.

    Article  PubMed  CAS  Google Scholar 

  14. Opas M, Szewczenko-Pawlikowski M, Jass GK, Mesaeli N, Michalak M. 1996. Calreticulin modulates cell adhesiveness via regulation of vinculin expression. J Cell Biol 135:1913-1923

    Article  PubMed  CAS  Google Scholar 

  15. Eadel MP, Dziak E, Lo CM, Ferrier J, Mesaeli N, Michalak M, Opas M. 1999. Calreticulin affects focal contact-dependent but not close contact-dependent cell-substratum adhesion. J Biol Chem 274:15085–15094.

    Article  Google Scholar 

  16. Fadel MP, Szewczenko-Pawlikowski M, Leclerc P, Dziak E, Symonds JM, Blaschuk O, Michalak M, Opas M. 2001. Calreticulin affects β-catenin associated pathways. J Biol Chem 276:27083–27089.

    Article  PubMed  CAS  Google Scholar 

  17. Liu N, Fine RE, Simons E, Johnson RJ. 1994. Decreasing calreticulin expression lowers the Ca2+ response to bradykinin and increases sensitivity to ionomycin in NG-108-15 cells. J Biol Chem 269:28635–28639.

    PubMed  CAS  Google Scholar 

  18. Bastianutto C, Clementi E, Codazzi F, Podini P, De Giorgi F, Rizzuto R, Meldolesi J, Pozzan T. 1995. Overexpression of calreticulin increases the Ca2+ capacity of rapidly exchanging Ca2+ stores and reveals aspects of their lumenal microenvironment and function. J Cell Biol 130:847–855.

    Article  PubMed  CAS  Google Scholar 

  19. Camacho P, Lechleiter JD. 1995. Calreticulin inhibits repetitive intracellular Ca2+ waves. Cell 82:765–771.

    Article  PubMed  CAS  Google Scholar 

  20. Mery L, Mesaeli N, Michalak M, Opas M, Lew DP, Krause K-H. 1996. Overexpression of calreticulin increases intracellular Ca2+ storage and decreases store-operated Ca2+ influx. J Biol Chem 271:9332–9339.

    Article  PubMed  CAS  Google Scholar 

  21. John LM, Lechleiter JD, Camacho P. 1998. Differential modulation of SERCA2 isoforms by calreticulin. J Cell Biol 142:963–973.

    Article  PubMed  CAS  Google Scholar 

  22. Fasolato C, Pizzo P, Pozzan T. 1998. Delayed activation of the store-operated calcium current induced by calreticulin overexpression in RBL-1 cells. Mol Biol Cell 9:1513–1522.

    PubMed  CAS  Google Scholar 

  23. Roderick HL, Lechleiter JD, Camacho P. 2000. Cytosolic phosphorylation of calnexin controls intracellular Ca2+ oscillations via an interaction with SERCA2b. J Cell Biol 149:1235–1248.

    Article  PubMed  CAS  Google Scholar 

  24. Xu W, Longo FJ, Wintermantel MR, Jiang X, Clark RA, DeLisle S. 2000. Calreticulin modulates capacitative Ca2+ influx by controlling the extent of inositol 1,4,5-trisphophate-induced Ca2+ store depletion. J Biol Chem 275:36676–36682.

    Article  PubMed  CAS  Google Scholar 

  25. Spiro RG, Zhu Q, Bhoyroo V, Söling H-D. 1996. Definition of the lectin-like properties of the molecular chaperone, calreticulin, and demonstration of its copurification with endomannosidase from rat liver Golgi. J Biol Chem 271:11588–11594.

    Article  PubMed  CAS  Google Scholar 

  26. Zapun A, Petrescu SM, Rudd PM, Dwek RA, Thomas DY, Bergeron JJM. 1997. Conformation-independent binding of monoglucosylated ribonuclease B to calnexin. Cell 88:29–38.

    Article  PubMed  CAS  Google Scholar 

  27. Vassilakos A, Michalak M, Lehrman MA, Wilhams DB. 1998. Oligosaccharide binding characteristics of the molecular chaperones calnexin and calreticuhn. Biochemistry 37:3480–3490.

    Article  PubMed  CAS  Google Scholar 

  28. Saito Y, Ihara Y, Leach MR, Cohen-Doyle MF, Wilhams DB. 1999. Calreticuhn functions in vitro as a molecular chaperone for both glycosylated and non-glycosylated proteins. EMBO J 18:6718–6729.

    Article  PubMed  CAS  Google Scholar 

  29. Thomas PJ, Qu BH, Pedersen PL. 1995. Defective protein folding as a basis of human disease. Trends Biochem Sci 20:456–459.

    Article  PubMed  CAS  Google Scholar 

  30. Brooks DA. 1997. otein processing: a role in the pathophysiology of genetic disease. FEBS Lett 409:115–120.

    Article  PubMed  CAS  Google Scholar 

  31. Brooks DA. 1999. Introduction: molecular chaperones of the ER: their role in protein folding and genetic disease. Semin Cell Dev Biol 10:441–442.

    Article  PubMed  CAS  Google Scholar 

  32. Gething MJ. 1999. Role and regulation of the ER chaperone BiP. Sem Cell Dev Biol 10:465–472.

    Article  CAS  Google Scholar 

  33. Halaban R, Svedine S, Cheng E, Smicun Y, Aron R, Hebert DN. 2000. Endoplasmic reticulum retention is a common defect associated with tyrosinase-negative albinism. Proc Natl Acad Sei USA 97:5889–5894.

    Article  CAS  Google Scholar 

  34. Rudd PM, Wormald MR, Wing DR, Prusiner SB, Dwek RA. 2001. Prion glycoprotein: structure, dynamics, and roles for the sugars. Biochemistry 40:3759–3766.

    Article  PubMed  CAS  Google Scholar 

  35. Rudd PM, Elliott T, Cresswell P, Wilson IA, Dwek RA. 2001. Glycosylation and the immune system. Science 291:2370–2376.

    Article  PubMed  CAS  Google Scholar 

  36. Sherman MY, Goldberg AL. 2001. Cellular defenses against unfolded proteins: a cell biologist thinks about neurodegenerative diseases. Neuron 29:15–32.

    Article  PubMed  CAS  Google Scholar 

  37. Baksh S, Michalak M. 1991. Expression of calreticulin in Escherichia coli and identification of its Ca2+ binding domains. J Biol Chem 266:21458–21465.

    PubMed  CAS  Google Scholar 

  38. Mesaeli N, Nakamura K, Zvaritch E, Dickie P, Dziak E, Krause K-H, Opas M, MacLennan DH, Michalak M. 1999. Calreticulin is essential for cardiac development. J Cell Biol 144:857–868.

    Article  PubMed  CAS  Google Scholar 

  39. Coppolino MG, Woodside MJ, Demaurex N, Grinstein S, St-Arnaud R, Dedhar S. 1997. Calreticulin is essential for integrin-mediated calcium signalling and cell adhesion. Nature 386:843–847.

    Article  PubMed  CAS  Google Scholar 

  40. Corbett EF, Oikawa K, Francois P, Tessier DC, Kay C, Bergeron JJM, Thomas DY, Krause K-H, Michalak M. 1999. Ca2+ regulation of interactions between endoplasmic reticulum chaperones. J Biol Chem 274:6203–6211.

    Article  PubMed  CAS  Google Scholar 

  41. Corbett EF, Michalak M. 2000. Calcium, a signaling molecule in the endoplasmic reticulum? Trends Biochem Sei 25:307–311.

    Article  CAS  Google Scholar 

  42. Corbett EF, Michalak KM, Oikawa K, Johnson S, Campbell ID, Eggleton P, Kay C, Michalak M. 2000. The conformation of calreticuhn is influenced by the endoplasmic reticulum lumenal environment. J Biol Chem 275:27177–27185.

    PubMed  CAS  Google Scholar 

  43. Fhegel L, Burns K, MacLennan DH, Reithmeier PJVF, Michalak M. 1989. Molecular cloning of the high affinity calcium-binding protein (calreticuhn) of skeletal muscle sarcoplasmic reticulum. J Biol Chem 264:21522–21528.

    Google Scholar 

  44. Milner RE, Baksh S, Shemanko C, Carpenter MR, Smillie L, Vance JE, Opas M, Michalak M. 1991. Calreticuhn, and not calsequestrin, is the major calcium binding protein of smooth muscle sarcoplasmic reticulum and liver endoplasmic reticulum. J Biol Chem 266:7155–7165.

    PubMed  CAS  Google Scholar 

  45. Tharin S, Dziak E, Michalak M, Opas M. 1992. Widespread tissue distribution of rabbit calreticulin, a non-muscle functional analogue of calsequestrin. Cell Tissue Res 269:29–37.

    Article  PubMed  CAS  Google Scholar 

  46. Imanaka-Yoshida K, Amitani A, Ioshii SO, Koyabu S, Yamakado T, Yoshida T. 1996. Alterations of expression and distribution of the Ca2+-storing proteins in endo/sarcoplasmic reticulum during differentiation of rat cardiomyocytes. J Mol Cell Cardiol 28:553–562.

    Article  PubMed  CAS  Google Scholar 

  47. Tsutsui H, Ishibashi Y, Imanaka-Yoshida K, Yamamoto S, Yoshida T, Urabe Y, Takeshita A. 1997. Alterations in sarcoplasmic reticulum calcium-storing proteins in pressure-overload cardiac hypertrophy. Am J Physiol 272:H168-H175.

    PubMed  CAS  Google Scholar 

  48. Chien KR, Zhu H, Knowlton KU, Miller-Hance W, van-Bilsen M, O’Brien TX, Evans SM. 1993. Transcriptional regulation during cardiac growth and development. Annu Rev Physiol 55:77–95.

    Article  PubMed  CAS  Google Scholar 

  49. Srivastava D, Cserjesi P, Olson EN. 1995. A subclass of bHLH proteins required for cardiac morphogenesis. Science 270:1995–1999.

    Article  PubMed  CAS  Google Scholar 

  50. Olson EN, Srivastava D. 1996. Molecular pathways controlling heart development. Science 272:671–676.

    Article  PubMed  CAS  Google Scholar 

  51. Sucov HM. 1998. Molecular insights into cardiac development. Annu Rev Physiol 60:287–308.

    Article  PubMed  CAS  Google Scholar 

  52. Tonissen KF, Drysdale TA, Lints TJ, Harvey RP, Krieg PA. 1994. XNkx-2.5, a Xenopus gene related to Nkx-2.5 and tinman: evidence for a conserved role in cardiac development. Dev Biol 162:325–328.

    Article  PubMed  CAS  Google Scholar 

  53. Patterson KD, Cleaver O, Gerber WV, Grow MW, Newman CS, Krieg PA. 1998. Homeobox genes in cardiovascular development. Curr Top Dev Biol 40:1–44.

    Article  PubMed  CAS  Google Scholar 

  54. Schwartz RJ, Olson EN. 1999. Building the heart piece by piece: modularity of cis-elements regulating Nkx2-5 transcription. Development 126:4187–4192.

    PubMed  CAS  Google Scholar 

  55. Evans SM. 1999. Vertebrate tinman homologues and cardiac differentiation. Semin Cell Dev Biol 10:73–83.

    Article  PubMed  CAS  Google Scholar 

  56. Edmondson DG, Lyons GE, Martin JF, Olson EN. 1994. Mef2 gene expression marks the cardiac and skeletal muscle lineages during mouse embryogenesis. Development 120:1251–1263.

    PubMed  CAS  Google Scholar 

  57. Ross RS, Navankasattusas S, Harvey RP, Chien KR. 1996. An HF-1 a/HF-1 b/MEF-2 combinatorial element confers cardiac ventricular specificity and established an anterior-posterior gradient of expression. Development 122:1799–1809.

    PubMed  CAS  Google Scholar 

  58. Fishman MC, Chien KR. 1997. Fashioning the vertebrate heart: earliest embryonic decisions. Development 124:2099–2117.

    PubMed  CAS  Google Scholar 

  59. Christensen TH, Kedes L. 1999. The myogenic regulatory circuit that controls cardiac/slow twitch troponin C gene transcription in skeletal muscle involves E-box, MEF-2, and MEF-3 motifs. Gene Expr 8:247–261.

    PubMed  CAS  Google Scholar 

  60. Schilham MW, Oosterwegel MA, Moerer P, Ya J, de Boer PA, van de Wetering M, Verbeek S, Lamers WH, Kruisbeek AM, Cumano A, Clevers, H. 1996. Defects in cardiac outflow tract formation and pro-B-lymphocyte expansion in mice lacking Sox-4. Nature 380:711–714.

    Article  PubMed  CAS  Google Scholar 

  61. Orkin SH. 1992. GATA-binding transcription factors in hematopoietic cells. Blood 80:575–581.

    PubMed  CAS  Google Scholar 

  62. Guo L, Lynch J, Nakamura K, Fliegel L, Kasahara H, Izumo S, Komuro I, Agellon LB, Michalak M. 2001. COUP-TF1 antagonizes Nkx2.5-mediated activation of the calreticulin gene during cardiac development. J Biol Chem 276:2797–2801.

    Article  PubMed  CAS  Google Scholar 

  63. Lyons I, Parsons LM, Hartley L, Li R, Andrews JE, Robb L, Harvey RP. 1995. Myogenic and mor-phogenetic defects in the heart tubes of murine embryos lacking the homeo box gene Nkx2-5. Genes Dev 9:1654–1666.

    Article  PubMed  CAS  Google Scholar 

  64. Grepin C, Dagnino L, Robitaille L, Haberstroh L, Antakly T, Nemer MA 1994. hormone-encoding gene identifies a pathway for cardiac but not skeletal muscle gene transcription. Mol Cell Biol 14:3115–3129.

    CAS  Google Scholar 

  65. Durocher D, Charron F, Warren R, Schwartz RJ, Nemer M. 1997. The cardiac transcription factors Nkx2-5 and GATA-4 are mutual cofactors. EMBO J 16:5687–5696.

    Article  PubMed  CAS  Google Scholar 

  66. Sepulveda JL, Belaguli N, Nigam V, Chen CY, Nemer M, Schwartz RJ. 1998. GATA-4 and Nkx-2.5 coactivate Nkx-2 DNA binding targets: role for regulating early cardiac gene expression. Mol Cell Biol 18:3405–3415.

    PubMed  CAS  Google Scholar 

  67. Timmerman LA, Clipstone NA, Ho SN, Northrop JP, Crabtree GR. 1996. Rapid shuttling of NF-AT in discrimination of Ca2+ signals and immunosuppression. Nature 383:837–840.

    Article  PubMed  CAS  Google Scholar 

  68. Dolmetsch RE, Lewis RS, Goodnow CC, Healy JI. 1997. Differential activation of transcription factors induced by Ca2+ response amplitude and duration. Nature 386:855–858.

    Article  PubMed  CAS  Google Scholar 

  69. Rao A, Luo C, Hogan PG. 1997. Transcription factors of the NFAT family: regulation and function. Annu Rev Immunol 15:707–747.

    Article  PubMed  CAS  Google Scholar 

  70. Molkentin JD, Lu JR, Antos CL, Markham B, Richardson J, Robbins J, Grant SR, Olson EN. 1998. A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell 93:215–228.

    Article  PubMed  CAS  Google Scholar 

  71. Mesaeh N, Nakamura K, Opas M, Michalak M. 2001. Endoplasmic reticulum in the heart, a forgotten organelle? Mol Cell Biochem 224:1–6.

    Article  Google Scholar 

  72. Jaconi M, Bony C, Richards SM, Terzic A, Arnaudeau S, Vassort G, Puceat M. 2000. Inositol 1,4,5-trisphosphate directs Ca2+ flow between mitochondria and the endoplasmic/sarcoplasmic reticulum: A role in regulating cardiac autonomic Ca2+ spiking. Mol Biol Cell 11:1845–1858.

    PubMed  CAS  Google Scholar 

  73. Lipp P, Laine M, Tovey SC, Burrell KM, Berridge MJ, Li W, Bootman MD. 2000. Functional InsP3 receptors that may modulate excitation-contraction coupling in the heart. Curr Biol 10:939–942.

    Article  PubMed  CAS  Google Scholar 

  74. Gros DB, Jongsma HJ. 1996. Connexins in mammalian heart function. Bioessays 18:719–730.

    Article  PubMed  CAS  Google Scholar 

  75. Kardami E, Doble BW. 1998. Cardiomyocyte gap junctions: a target for growth factor signaling. Trends Cardiovasc Med 8:180–187.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Canadian Institutes of Health Research Membrane, Protein Research Group and the Department of Biochemistry, University of Alberta, Edmonton, Alberta, T6G 2H7, Canada

    Barbara Knoblach & Dr. Marek Michalak

  2. Department of Pediatrics, Kumamoto University School of Medicine, Honjo 1-1-1, Kumamoto, Japan

    Kimitoshi Nakamura

  3. Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada, T6G 2H7

    Murray Robertson

Authors
  1. Barbara Knoblach
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  2. Kimitoshi Nakamura
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  3. Murray Robertson
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  4. Dr. Marek Michalak
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Correspondence to Marek Michalak .

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Editors and Affiliations

  1. Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre Faculty of Medicine, University of Manitoba, Winnipeg, Canada

    Naranjan S. Dhalla PhD, MD (Hon), DSc (Hon) (Distinguished Professor and Director), Larry V. Hryshko PhD (Associate Professor), Elissavet Kardami PhD (Professor) & Pawan K. Singal PhD, DSc (Professor) (Distinguished Professor and Director),  (Associate Professor),  (Professor) &  (Professor)

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Knoblach, B., Nakamura, K., Robertson, M., Michalak, M. (2003). Calreticulin, Cardiac Development and Congenital Complete Heart Block in Children. In: Dhalla, N.S., Hryshko, L.V., Kardami, E., Singal, P.K. (eds) Signal Transduction and Cardiac Hypertrophy. Progress in Experimental Cardiology, vol 7. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-0347-7_8

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