1. Department of Biological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan
2. Department of Medical Chemistry, Graduate School of Medicine, Tohoku University, Miyagi 980-8575, Japan
3. Department of Physiology and Biophysics, Robert Wood Johnson Medical School, New Jersey 08854, USA
4. Neuroscience Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Ibaraki 305-8568, Japan
5. PRESTO, Japan Science and Technology Agency, Saitama 332-0012, Japan
6. Department of Anatomy, Saitama Medical University, Saitama 350-0495, Japan

Correspondence to: Hiroshi Takeshima^1,2 Correspondence and requests for materials should be addressed to H.T. (Email: takeshim@pharm.kyoto-u.ac.jp).

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⁺ release^{1, 2, 3, 4, 5, 6, 7}. Ca²⁺ release channels were cloned more than 15 years ago^{8, 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.