A study on the molecular hasis of intracellular Ca^<2+> stores

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Cell signaling requires efficient Ca^<2+> mobilization from intracellular stores through Ca^<2+> release channels, as well as predicted counter movement of ions across the sarcoplasmic/endoplasmic reticulum (SR/ER) membrane to balance the transient negative potential generated by Ca^<2+> release^<1-7>. Ca^<2+> release channels were cloned more than 15 years ago^<8,9>, whereas molecular identity of putative counterion 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 display severe dysfunction in intracellular Ca^<2+> handling. The TRIO-deficient skeletal muscle SR shows reduced K+ permeability, as well as altered Ca^<2+> spark signaling and voltage-induced Ca^<2+> release. Therefore, TRIC channels correspond closely to the long-sought counter-ion channels that function in synchronization with SR/ER Ca^<2+> release.