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