Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

TRIC channels are essential for Ca2+ handling in intracellular stores

Nature volume 448, pages 78–82 (2007)Cite this article

Abstract

Cell signalling requires efficient Ca2+ mobilization from intracellular stores through Ca2+ release channels, as well as predicted counter-movement of ions across the sarcoplasmic/endoplasmic reticulum membrane to balance the transient negative potential generated by Ca2+ release1,2,3,4,5,6,7. Ca2+ release channels were cloned more than 15 years ago8,9, whereas the molecular identity of putative counter-ion channels remains unknown. Here we report two TRIC (trimeric intracellular cation) channel subtypes that are differentially expressed on intracellular stores in animal cell types. TRIC subtypes contain three proposed transmembrane segments, and form homo-trimers with a bullet-like structure. Electrophysiological measurements with purified TRIC preparations identify a monovalent cation-selective channel. In TRIC-knockout mice suffering embryonic cardiac failure, mutant cardiac myocytes show severe dysfunction in intracellular Ca2+ handling. The TRIC-deficient skeletal muscle sarcoplasmic reticulum shows reduced K+ permeability, as well as altered Ca2+ ‘spark’ signalling and voltage-induced Ca2+ release. Therefore, TRIC channels are likely to act as counter-ion channels that function in synchronization with Ca2+ release from intracellular stores.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Biochemical characterization of TRIC subtypes.
Figure 2: Electrophysiological characterization of the TRIC-A channel.
Figure 3: Physiological abnormalities in TRIC-knockout hearts.
Figure 4: Compromised Ca 2+ release and altered membrane potential in TRIC-deficient skeletal muscle SR.

Similar content being viewed by others

References

  1. Ebashi, S. Excitation-contraction coupling. Annu. Rev. Physiol. 38, 293–313 (1976)

    Article  CAS  Google Scholar 

  2. Berridge, M. J. The endoplasmic reticulum: a multifunctional signaling organelle. Cell Calcium 32, 235–249 (2002)

    Article  CAS  Google Scholar 

  3. Fill, M. & Copello, J. A. Ryanodine receptor calcium release channels. Physiol. Rev. 82, 893–922 (2002)

    Article  CAS  Google Scholar 

  4. Somlyo, A. V., Shuman, H. & Somlyo, A. P. Composition of sarcoplasmic reticulum in situ by electron probe X-ray microanalysis. Nature 268, 556–558 (1977)

    Article  CAS  ADS  Google Scholar 

  5. Coronado, R. & Miller, C. Decamethonium and hexamethonium block K+ channels of sarcoplasmic reticulum. Nature 288, 495–497 (1980)

    Article  CAS  ADS  Google Scholar 

  6. Fink, R. H. & Veigel, C. Calcium uptake and release modulated by counter-ion conductances in the sarcoplasmic reticulum of skeletal muscle. Acta Physiol. Scand. 156, 387–396 (1996)

    Article  CAS  Google Scholar 

  7. Meissner, G. Monovalent ion and calcium ion fluxes in sarcoplasmic reticulum. Mol. Cell. Biochem. 55, 65–82 (1983)

    Article  CAS  Google Scholar 

  8. Takeshima, H. et al. Primary structure and expression from complementary DNA of skeletal muscle ryanodine receptor. Nature 339, 439–445 (1989)

    Article  CAS  ADS  Google Scholar 

  9. Furuichi, T. et al. Primary structure and functional expression of the inositol 1,4,5-trisphosphate-binding protein P400. Nature 342, 32–38 (1989)

    Article  CAS  ADS  Google Scholar 

  10. Takeshima, H. et al. Mitsugumin29, a novel synaptophysin family member from the triad junction in skeletal muscle. Biochem. J. 331, 317–322 (1998)

    Article  CAS  Google Scholar 

  11. Takeshima, H. et al. Junctophilins: a novel family of junctional membrane complex proteins. Mol. Cell 6, 11–22 (2000)

    CAS  PubMed  Google Scholar 

  12. Dani, J. A. & Mayer, M. L. Structure and function of glutamate and nicotinic acetylcholine receptors. Curr. Opin. Neurobiol. 5, 310–317 (1995)

    Article  CAS  Google Scholar 

  13. Ogura, T. & Sato, C. Auto-accumulation method using simulated annealing enables fully automatic particle pickup completely free from a matching template or learning data. J. Struct. Biol. 146, 344–358 (2004)

    Article  Google Scholar 

  14. Ogura, T. & Sato, C. Automatic particle pickup method using a neural network has high accuracy by applying an initial weight derived from eigenimages: a new reference free method for single-particle analysis. J. Struct. Biol. 145, 63–75 (2004)

    Article  CAS  Google Scholar 

  15. Ogura, T., Iwasaki, K. & Sato, C. Topology representing network enables highly accurate classification of protein images taken by cryo electron-microscope without masking. J. Struct. Biol. 143, 185–200 (2003)

    Article  CAS  Google Scholar 

  16. van Heel, M. et al. Single-particle electron cryo-microscopy: towards atomic resolution. Q. Rev. Biophys. 33, 307–369 (2000)

    Article  CAS  Google Scholar 

  17. Mio, K. et al. Visualization of the trimeric P2X2 receptor with a crown-capped extracellular domain. Biochem. Biophys. Res. Commun. 337, 998–1005 (2005)

    Article  CAS  Google Scholar 

  18. Cowan, S. W. et al. Crystal structures explain functional properties of two E. coli porins. Nature 358, 727–733 (1992)

    Article  CAS  ADS  Google Scholar 

  19. Liu, Q.-Y. et al. Reconstitution of the solubilized cardiac sarcoplasmic reticulum potassium channel identification of a putative Mr ∼80 kDa polypeptide constituent. FEBS Lett. 291, 13–16 (1991)

    Article  CAS  Google Scholar 

  20. Takeshima, H. et al. Embryonic lethality and abnormal cardiac myocytes in mice lacking ryanodine receptor type 2. EMBO J. 17, 3309–3316 (1998)

    Article  CAS  Google Scholar 

  21. Endo, M. Calcium release from the sarcoplasmic reticulum. Physiol. Rev. 57, 71–108 (1977)

    Article  CAS  Google Scholar 

  22. Meissner, G. Ryanodine receptor/Ca2+ release channels and their regulation by endogenous effectors. Annu. Rev. Physiol. 56, 485–508 (1994)

    Article  CAS  Google Scholar 

  23. Fabiato, A. Calcium-induced release of calcium from the cardiac sarcoplasmic reticulum. Am. J. Physiol. 245, C1–C14 (1983)

    Article  CAS  Google Scholar 

  24. Antoon, F. M. et al. Presence of functional sarcoplasmic reticulum in the developing heart and its confinement to chamber myocardium. Dev. Biol. 223, 279–290 (2000)

    Article  Google Scholar 

  25. Wang, X. et al. Uncontrolled calcium sparks act as a dystrophic signal for mammalian skeletal muscle. Nature Cell Biol. 7, 525–530 (2005)

    Article  CAS  Google Scholar 

  26. Weisleder, N. et al. Muscle aging is associated with compromised Ca2+ spark signaling and segregated intracellular Ca2+ release. J. Cell Biol. 174, 639–645 (2006)

    Article  CAS  Google Scholar 

  27. Collet, C. et al. Intracellular calcium signals measured with indo-1 in isolated skeletal muscle fibers from control and mdx mice. J. Physiol. (Lond.) 520, 417–429 (1999)

    Article  CAS  Google Scholar 

  28. Toyoshima, C. & Inesi, G. Structural basis of ion pumping by Ca2+-ATPase of the sarcoplasmic reticulum. Annu. Rev. Biochem. 73, 269–292 (2004)

    Article  CAS  Google Scholar 

  29. Meissner, G. & Young, R. C. Proton permeability of sarcoplasmic reticulum vesicles. J. Biol. Chem. 255, 6814–6819 (1980)

    CAS  PubMed  Google Scholar 

  30. Kourie, J. I. et al. Characteristics of two types of chloride channel in sarcoplasmic reticulum vesicles from rabbit skeletal muscle. Biophys. J. 70, 202–221 (1996)

    Article  CAS  ADS  Google Scholar 

  31. Saito, A. et al. Preparation and morphology of sarcoplasmic reticulum terminal cisternae from rabbit skeletal muscle. J. Cell Biol. 99, 875–885 (1984)

    Article  CAS  Google Scholar 

  32. Fernandez, J. L., Rosemblatt, M. & Hidalgo, C. Highly purified sarcoplasmic reticulum vesicles are devoid of Ca2+-independent (‘basal’) ATPase activity. Biochim. Biophys. Acta 599, 552–568 (1980)

    Article  CAS  Google Scholar 

  33. Zhang, M. et al. Calumin, a novel Ca2+-binding transmembrane protein on the endoplasmic reticulum. Cell Calcium (in the press)

  34. Feramisco, J. D., Goldstein, J. L. & Brown, M. S. Membrane topology of human Insig-1, a protein regulator of lipid synthesis. J. Biol. Chem. 279, 8487–8496 (2004)

    Article  CAS  Google Scholar 

  35. Faulk, W. P. & Taylor, G. M. An immunocolloid method for the electron microscope. Immunochemistry 8, 1081–1083 (1971)

    Article  CAS  Google Scholar 

  36. Frank, J. Three-dimensional Electron Microscopy of Macromolecular Assemblies (Oxford Univ. Press, New York, 2006)

  37. Harauz, G. & van Heel, M. Exact filters for general geometry three dimensional reconstruction. Optik 73, 146–156 (1986)

    Google Scholar 

  38. Ma, J. Block by ruthenium red of the ryanodine-activated calcium release channel of skeletal muscle. J. Gen. Physiol. 102, 1031–1056 (1993)

    Article  CAS  Google Scholar 

  39. Takeshima, H. et al. Excitation-contraction uncoupling and muscular degeneration in mice lacking functional skeletal muscle ryanodine-receptor gene. Nature 369, 556–559 (1994)

    Article  CAS  ADS  Google Scholar 

  40. Li, E., Bestor, T. H. & Jaenish, R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69, 915–926 (1992)

    CAS  Google Scholar 

Download references

Acknowledgements

We thank M. Kameyama for technical assistance, M. Fill and G. Meissner for suggestions, K. Hirose for close cooperation in electron microscopy studies, H. Masumiya for help with the lipid bilayer measurements, and T. Iwamoto for providing anti-NCX1 antibody. This work was supported in part by the Ministry of Education, Culture, Sports, Science and Technology of Japan, the Japan Science and Technology Agency, the Ministry of Health and Welfare of Japan, the Japan New Energy and Industrial Technology Development Organization, the Naito Foundation, the Sumitomo Foundation, the Uehara Memorial Foundation, the Takeda Science Foundation, and the National Institutes of Health.

Author Contributions M.Y., J.F. and M.Z. conducted biochemical experiments and characterized TRIC-DKO mice. K.M., T.O. and C.S. reconstructed the three-dimensional structure. M.Y., Z.P. and J.M. conducted bilayer measurements. C.F., P-H.L., N.W., X.Z. and J.M. characterized TRIC-deficient skeletal muscle. S.K. was responsible for histology. K.K., M.N. and H.T. identified TRIC subtypes and produced knockout mice. H.T. oversaw the project.

Sequence data for rabbit and mouse TRIC channel cDNAs have been deposited in the DDBJ/NCBI/EMBL nucleotide databases under accession numbers of AB261158–AB261160.

Author information

Authors and Affiliations

  1. Department of Biological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan,

    Masayuki Yazawa, Miao Zhang, Miyuki Nishi & Hiroshi Takeshima

  2. Department of Medical Chemistry, Graduate School of Medicine, Tohoku University, Miyagi 980-8575, Japan,

    Masayuki Yazawa, Jue Feng, Miao Zhang, Kazuhiro Kato, Miyuki Nishi & Hiroshi Takeshima

  3. Department of Physiology and Biophysics, Robert Wood Johnson Medical School, New Jersey 08854, USA,

    Christopher Ferrante, Pei-Hui Lin, Zui Pan, Xiaoli Zhao, Noah Weisleder & Jianjie Ma

  4. Neuroscience Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Ibaraki 305-8568, Japan,

    Kazuhiro Mio, Toshihiko Ogura & Chikara Sato

  5. PRESTO, Japan Science and Technology Agency, Saitama 332-0012, Japan,

    Toshihiko Ogura

  6. Department of Anatomy, Saitama Medical University, Saitama 350-0495, Japan,

    Shinji Komazaki

Authors
  1. Masayuki Yazawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christopher Ferrante
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jue Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kazuhiro Mio
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Toshihiko Ogura
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Miao Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Pei-Hui Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Zui Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Shinji Komazaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Kazuhiro Kato
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Miyuki Nishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Xiaoli Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Noah Weisleder
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Chikara Sato
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Jianjie Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Hiroshi Takeshima
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hiroshi Takeshima.

Ethics declarations

Competing interests

Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

This file includes Supplementary Figures S1-S10 with Legends. (PDF 1671 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yazawa, M., Ferrante, C., Feng, J. et al. TRIC channels are essential for Ca2+ handling in intracellular stores. Nature 448, 78–82 (2007). https://doi.org/10.1038/nature05928

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature05928

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing