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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.

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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.

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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.

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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

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Correspondence to Hiroshi Takeshima.

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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

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