Skip to main content

Advertisement

SpringerLink
Log in

Altered calsequestrin glycan processing is common to diverse models of canine heart failure

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Calsequestrin-2 (CSQ2) is a resident glycoprotein of junctional sarcoplasmic reticulum that functions in the regulation of SR Ca2+ release. CSQ2 is biosynthesized in rough ER around cardiomyocyte nuclei and then traffics transversely across SR subcompartments. During biosynthesis, CSQ2 undergoes N-linked glycosylation and phosphorylation by protein kinase CK2. In mammalian heart, CSQ2 molecules subsequently undergo extensive mannose trimming by ER mannosidase(s), a posttranslational process that often regulates protein breakdown. We analyzed the intact purified CSQ2 from mongrel canine heart tissue by electrospray mass spectrometry. The average molecular mass of CSQ2 in normal mongrel dogs was 46,306 ± 41 Da, corresponding to glycan trimming of 3–5 mannoses, depending upon the phosphate content. We tested whether CSQ2 glycan structures would be altered in heart tissue from mongrel dogs induced into heart failure (HF) by two very different experimental treatments, rapid ventricular pacing or repeated coronary microembolizations. Similarly dramatic changes in mannose trimming were found in both types of induced HF, despite the different cardiomyopathies producing the failure. Unique to all samples analyzed from HF dog hearts, 20–40 % of all CSQ2 contained glycans that had minimal mannose trimming (Man9,8). Analyses of tissue samples showed decreases in CSQ2 protein levels per unit levels of mRNA for tachypaced heart tissue, also indicative of altered turnover. Quantitative immunofluorescence microscopy of frozen tissue sections suggested that no changes in CSQ2 levels occurred across the width of the cell. We conclude that altered processing of CSQ2 may be an adaptive response to the myocardium under stresses that are capable of inducing heart failure.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Houser SR, Piacentino V 3rd, Weisser J (2000) Abnormalities of calcium cycling in the hypertrophied and failing heart. J Mol Cell Cardiol 32:1595–1607

    Article  CAS  PubMed  Google Scholar 

  2. Sjaastad I, Wasserstrom JA, Sejersted OM (2003) Heart failure: a challenge to our current concepts of excitation-contraction coupling. J Physiol 546:33–47

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Bers DM, Eisner DA, Valdivia HH (2003) Sarcoplasmic reticulum Ca2+ and heart failure: roles of diastolic leak and Ca2+ transport. Circ Res 93:487–490

    Article  CAS  PubMed  Google Scholar 

  4. Wu X, Zhang T, Bossuyt J, Li X, McKinsey TA, Dedman JR, Olson EN, Chen J, Brown JH, Bers DM (2006) Local InsP3-dependent perinuclear Ca2+ signaling in cardiac myocyte excitation-transcription coupling. J Clin Invest 116:675–682

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Houser SR, Molkentin JD (2008) Does contractile Ca2+ control calcineurin-NFAT signaling and pathological hypertrophy in cardiac myocytes? Sci Signal 1(25):pe31

    Google Scholar 

  6. Goonasekera SA, Molkentin JD (2012) Unraveling the secrets of a double life: contractile versus signaling Ca2+ in a cardiac myocyte. J Mol Cell Cardiol 52:317–322

    Article  CAS  PubMed  Google Scholar 

  7. Li T, Danelisen I, Singal PK (2002) Early changes in myocardial antioxidant enzymes in rats treated with adriamycin. Mol Cell Biochem 232:19–26

    Article  CAS  PubMed  Google Scholar 

  8. Nakayama H, Bodi I, Maillet M, DeSantiago J, Domeier TL, Mikoshiba K, Lorenz JN, Blatter LA, Bers DM, Molkentin JD (2010) The IP3 receptor regulates cardiac hypertrophy in response to select stimuli. Circ Res 107:659–666

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zhang L, Kelley J, Schmeisser G, Kobayashi YM, Jones LR (1997) Complex formation between junctin, triadin, calsequestrin, and the ryanodine receptor. Proteins of the cardiac junctional sarcoplasmic reticulum membrane. J Biol Chem 272:23389–23397

    Article  CAS  PubMed  Google Scholar 

  10. Terentyev D, Viatchenko-Karpinski S, Gyorke I, Volpe P, Williams SC, Gyorke S (2003) Calsequestrin determines the functional size and stability of cardiac intracellular calcium stores: mechanism for hereditary arrhythmia. Proc Natl Acad Sci USA 100:11759–11764

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Knollmann BC (2009) New roles of calsequestrin and triadin in cardiac muscle. J Physiol 587:3081–3087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. McFarland TP, Milstein ML, Cala SE (2010) Rough endoplasmic reticulum to junctional sarcoplasmic reticulum trafficking of calsequestrin in adult cardiomyocytes. J Mol Cell Cardiol 49:556–564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Guo A, Cala SE, Song LS (2012) Calsequestrin accumulation in rough endoplasmic reticulum promotes perinuclear Ca2+ release. J Biol Chem 287:16670–16680

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. McFarland TP, Sleiman NH, Yaeger DB, Cala SE (2011) The cytosolic protein kinase CK2 phosphorylates cardiac calsequestrin in intact cells. Mol Cell Biochem 353:81–91

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. O’Brian JJ, Ram ML, Kiarash A, Cala SE (2002) Mass spectrometry of cardiac calsequestrin characterizes microheterogeneity unique to heart and indicative of complex intracellular transit. J Biol Chem 277:37154–37160

    Article  PubMed  Google Scholar 

  16. Kiarash A, Kelly C, Phinney B, Valdivia H, Abrams J, Cala S (2004) Defective glycosylation of calsequestrin in heart failure. Cardiovasc Res 63:264–272

    Article  CAS  PubMed  Google Scholar 

  17. Sabbah HN, Stein PD, Kono T, Gheorghiade M, Levine TB, Jafri S, Hawkins ET, Goldstein S (1991) A canine model of chronic heart failure produced by multiple sequential coronary microembolizations. Am J Physiol 260:H1379–H1384

    CAS  PubMed  Google Scholar 

  18. Sala-Mercado JA, Ichinose M, Coutsos M, Li Z, Fano D, Ichinose T, Dawe EJ, O’Leary DS (2010) Progressive muscle metaboreflex activation gradually decreases spontaneous heart rate baroreflex sensitivity during dynamic exercise. Am J Physiol Heart Circ Physiol 298:H594–H600

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680–685

    Article  CAS  PubMed  Google Scholar 

  20. Lowry HO, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurements with folin phenol reagent. J Biol Chem 193:265–275

    CAS  PubMed  Google Scholar 

  21. Terentyev D, Cala SE, Houle TD, Viatchenko-Karpinski S, Gyorke I, Terentyeva R, Williams SC, Gyorke S (2005) Triadin overexpression stimulates excitation-contraction coupling and increases predisposition to cellular arrhythmia in cardiac myocytes. Circ Res 96:651–658

    Article  CAS  PubMed  Google Scholar 

  22. Clegg JC (1982) Glycoprotein detection in nitrocellulose transfers of electrophoretically separated protein mixtures using concanavalin A and peroxidase: application to arenavirus and flavivirus proteins. Anal Biochem 127:389–394

    Article  CAS  PubMed  Google Scholar 

  23. Ram ML, Kiarash A, Marsh JD, Cala SE (2004) Phosphorylation and dephosphorylation of calsequestrin on CK2-sensitive sites in heart. Mol Cell Biochem 266:209–217

    Article  CAS  PubMed  Google Scholar 

  24. Fagioli C, Sitia R (2001) Glycoprotein quality control in the endoplasmic reticulum. Mannose trimming by endoplasmic reticulum mannosidase I times the proteasomal degradation of unassembled immunoglobulin subunits. J Biol Chem 276:12885–12892

    Article  CAS  PubMed  Google Scholar 

  25. Helenius A, Aebi M (2001) Intracellular functions of N-linked glycans. Science 291:2364–2369

    Article  CAS  PubMed  Google Scholar 

  26. Houle TD, Ram ML, McMurray WJ, Cala SE (2006) Different endoplasmic reticulum trafficking and processing pathways for calsequestrin (CSQ) and epitope-tagged CSQ. Exp Cell Res 312:4150–4161

    Article  CAS  PubMed  Google Scholar 

  27. Bhattacharyya L, Koenig SH, Brown RD 3rd, Brewer CF (1991) Interactions of asparagine-linked carbohydrates with concanavalin A. Nuclear magnetic relaxation dispersion and circular dichroism studies. J Biol Chem 266:9835–9840

    Google Scholar 

  28. Cala SE, Jones LR (1991) Phosphorylation of cardiac and skeletal muscle calsequestrin isoforms by casein kinase II. Demonstration of a cluster of unique rapidly phosphorylated sites in cardiac calsequestrin. J Biol Chem 266:391–398

    CAS  PubMed  Google Scholar 

  29. McCall E, Ginsburg KS, Bassani RA, Shannon TR, Qi M, Samarel AM, Bers DM (1998) Ca flux, contractility, and excitation-contraction coupling in hypertrophic rat ventricular myocytes. Am J Physiol 274:H1348–H1360

    CAS  PubMed  Google Scholar 

  30. Gomez AM, Valdivia HH, Cheng H, Lederer MR, Santana LF, Cannell MB, McCune SA, Altschuld RA, Lederer WJ (1997) Defective excitation-contraction coupling in experimental cardiac hypertrophy and heart failure. Science 276:800–806

    Article  CAS  PubMed  Google Scholar 

  31. Damiano RJ Jr, Tripp HF Jr, Asano T, Small KW, Jones RH, Lowe JE (1987) Left ventricular dysfunction and dilatation resulting from chronic supraventricular tachycardia. J Thorac Cardiovasc Surg 94:135–143

    PubMed  Google Scholar 

  32. Tomita M, Spinale FG, Crawford FA, Zile MR (1991) Changes in left ventricular volume, mass, and function during the development and regression of supraventricular tachycardia-induced cardiomyopathy. Disparity between recovery of systolic versus diastolic function. Circulation 83:635–644

    Article  CAS  PubMed  Google Scholar 

  33. Slade AM, Server NJ (1985) Rough endoplasmic reticulum in the adult mammalian cardiac muscle cell. J Submicrosc Cytol 17:531–536

    Google Scholar 

  34. Wang X, Johnsson N (2005) Protein kinase CK2 phosphorylates Sec63p to stimulate the assembly of the endoplasmic reticulum protein translocation apparatus. J Cell Sci 118:723–732

    Article  CAS  PubMed  Google Scholar 

  35. Lakkaraju AK, Abrami L, Lemmin T, Blaskovic S, Kunz B, Kihara A, Dal Peraro M, van der Goot FG (2012) Palmitoylated calnexin is a key component of the ribosome-translocon complex. EMBO J 31:1823–1835

    Google Scholar 

  36. Chevet E, Wong HN, Gerber D, Cochet C, Fazel A, Cameron PH, Gushue JN, Thomas DY, Bergeron JJ (1999) Phosphorylation by CK2 and MAPK enhances calnexin association with ribosomes. EMBO J 18:3655–3666

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hauck L, Harms C, An J, Rohne J, Gertz K, Dietz R, Endres M, von Harsdrof R (2008) Protein kinase CK2 links extracellular growth factor signaling with the control of p27(Kip1) stability in the heart. Nat Med 14:315–324

    Google Scholar 

  38. Song LS, Sobie EA, McCulle S, Lederer WJ, Balke CW, Cheng H (2006) Orphaned ryanodine receptors in the failing heart. Proc Natl Acad Sci USA 103:4305–4310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wei S, Guo A, Chen B, Kutschke W, Xie YP, Zimmerman K, Weiss RM, Anderson ME, Cheng H, Song LS (2010) T-tubule remodeling during transition from hypertrophy to heart failure. Circ Res 107:520–531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Balijepalli RC, Lokuta AJ, Maertz NA, Buck JM, Haworth RA, Valdivia HH, Kamp TJ (2003) Depletion of T-tubules and specific subcellular changes in sarcolemmal proteins in tachycardia-induced heart failure. Cardiovasc Res 59:67–77

    Article  CAS  PubMed  Google Scholar 

  41. Wu HD, Xu M, Li RC, Guo L, Lai YS, Xu SM, Li SF, Lu QL, Li LL, Zhang HB, Zhang YY, Zhang CM, Wang SQ (2012) Ultrastructural remodelling of Ca(2+) signalling apparatus in failing heart cells. Cardiovasc Res 95:430–438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We gratefully acknowledge expert technical assistance from Lauren Dovantsis. We thank Jeffrey J. O’Brian, M.D., Ph.D. (Indiana University Health Ball Memorial Hospital) for critical reading of the manuscript. This work was supported by NIH R01 HL062586 to SEC.

Author information

Authors and Affiliations

  1. Division of Cardiology/Electrophysiology, Department of Internal Medicine, Wayne State University, Detroit, MI, 48201, USA

    Sony Jacob

  2. Department of Physiology, Wayne State University School of Medicine, Detroit, MI, 48201, USA

    Naama H. Sleiman, Stephanie Kern, Javier A. Sala-Mercado, Timothy P. McFarland & Steven E. Cala

  3. Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Larry R. Jones

  4. Cardiovascular Research Institute, Wayne State University, Detroit, MI, 48201, USA

    Javier A. Sala-Mercado & Steven E. Cala

  5. Cardiovascular Research Division, Henry Ford Health Systems, Detroit, MI, 48202, USA

    Hani H. Sabbah

Authors
  1. Sony Jacob
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Naama H. Sleiman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stephanie Kern
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Larry R. Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Javier A. Sala-Mercado
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Timothy P. McFarland
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hani H. Sabbah
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Steven E. Cala
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Steven E. Cala.

Additional information

Sony Jacob and Naama H. Sleiman contributed equally to this study.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jacob, S., Sleiman, N.H., Kern, S. et al. Altered calsequestrin glycan processing is common to diverse models of canine heart failure. Mol Cell Biochem 377, 11–21 (2013). https://doi.org/10.1007/s11010-013-1560-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-013-1560-7

Keywords

Search

Navigation