TRIC channels are essential for Ca2+ handling in intracellular stores

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. Ca2+ release channels were cloned more than 15 years ago, 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.

Osteogenesis imperfecta

“…TRIC B is a monovalent cation specific channel that is necessary for intracellu lar calcium flux and is involved in cell differentiation 95 . Tmem38b −/− mice are neonatally lethal and have reduced bone volume 95,96 . Defective ER calcium flux dysregulates collagen synthesis by multiple ER enzymes 94,97 (FIG.…”

TRIC-B Mutations Causing Osteogenesis Imperfecta

“…Double-knockout mice lacking both the subtypes die during early embryonic stages, and RyR-mediated Ca 2+ release is weakened in the mutant cardiomyocytes. 4) In Tric-a-knockout mice, the mutant vascular smooth muscle shows poor RyRmediated Ca 2+ sparks, 9,10) and the mutant skeletal muscle exhibits 'alternan' contractile responses which are likely generated due to compromised RyR-mediated Ca 2+ release.…”

“…300 amino acid residues, three membrane-spanning segments are predicted, and the amino-and carboxyl-termini are assigned to the luminal and cytoplasmic sides, respectively. 4) Moreover, TRIC-A preparations purified from both skeletal muscle and recombinant bacteria exhibit bullet-shaped homo-trimeric complexes, and form functional monovalent cation-selective channels in artificial lipid bilayers. 4,5) Skeletal and cardiac muscle SR contains the well-known decamethonium-sensitive SR K + channel, 6) which vaguely resembles TRIC subtypes in certain electrophysiological characteristics.…”

“…4) Moreover, TRIC-A preparations purified from both skeletal muscle and recombinant bacteria exhibit bullet-shaped homo-trimeric complexes, and form functional monovalent cation-selective channels in artificial lipid bilayers. 4,5) Skeletal and cardiac muscle SR contains the well-known decamethonium-sensitive SR K + channel, 6) which vaguely resembles TRIC subtypes in certain electrophysiological characteristics. However, TRIC subtypes are unlikely to form the authentic decamethonium-sensitive K + channel, because the recording frequency and gating features of the SR K + channel are not altered in SR preparations from Tric-a-knockout mice.…”

“…[1][2][3] TRIC channel subtypes have also been identified in this molecular search. 4) TRIC-A is preferentially expressed in excitable tissues, particularly in skeletal and cardiac muscle cells, and localized in the SR and nuclear envelope. Meanwhile, TRIC-B is ubiquitously distributed throughout tissues at moderate expression levels.…”