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1.A.62 The Homotrimeric Cation Channel (TRIC) Family

Eukaryotic 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 has been unknown. Two channel sub-types are differentially expressed in 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 identified 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.

TRIC-A is preferentially expressed in excitable tissues, including striated muscle and brain, whereas TRIC-B is present in most mammalian tissues. TRIC-A is distributed throughout the sarcoplasmic reticulum (SR) and nuclear membranes in skeletal muscle, and TRIC-B behaved as an endoplasmic reticulum (ER)-resident protein in brain tissues. Therefore, TRIC subtypes are localized to membrane systems associated with intracellular Ca2+ stores.

TRIC subtypes show conserved hydropathicity profiles that suggest multiple transmembrane segments. In limited proteolysis analysis using membrane vesicles, Yazawa et al. (2007) found that the amino terminus of TRIC-A is located in the SR/ER lumen, whereas the carboxy terminus is exposed to the cytoplasm. Yazawa et al. (2007) predicted three transmembrane segments in TRIC-A with a hydrophobic loop as a candidate for an ion-conducting pore between the first and second transmembrane segments. The proposed topology of TRIC subtypes bears an overall resemblance to that of glutamate receptor channels.

The TRIC family includes a profusion of prokaryotic family members with topologies and motifs similar to those of their eukaryotic counterparts. Prokaryotic members far outnumber eukaryotic members and possibly function as secondary carriers (Silverio and Saier, 2011). The presence of fused N- or C-terminal domains of known biochemical functions as well as genomic context analyses provided clues about the functions of these prokaryotic homologs. They may mediate metabolite (e.g., amino acid/nucleotide) efflux. Phylogenetic analyses revealed that TRIC channel homologs diverged relatively early during evolutionary history and that horizontal gene transfer was frequent in prokaryotes but rare in eukaryotes. Topological analyses of TRIC channels revealed that these proteins possess seven transmembrane segments (TMSs), which arose by intragenic duplication of a three-TMS polypeptide-encoding genetic element followed by addition of a seventh TMS at the C terminus to give the precursor of all current TRIC family homologs (Silverio and Saier, 2011). 

TRIC-A and TRIC-B modulate the release of Ca2+ through the ryanodine receptor or inositol triphosphate receptor and maintain the homeostasis of ions within the SR/ER lumen. Genetic ablations or mutations of TRIC channels are associated with hypertension, heart disease, respiratory defects and brittle bone disease. Yang et al. 2016 presented the structures of TRIC-B1 and TRIC-B2 channels from Caenorhabditis elegans in complex with endogenous phosphatidylinositol-4,5-biphosphate (PtdIns(4,5)P2, also known as PIP2) lipid molecules. The TRIC-B1/B2 proteins and PIP2 assemble into a symmetrical homotrimeric complex. Each monomer contains an hourglass-shaped hydrophilic pore contained within a seven-transmembrane-helix domain. Structural and functional analyses revealed the central role of PIP2 in stabilizing the cytoplasmic gate of the ion permeation pathway and showed a marked Ca2+-induced conformational change in a cytoplasmic loop above the gate. A mechanistic model was proposed to account for the complex gating mechanism of TRIC channels (Yang et al. 2016). 

Ca2+ release from the sarcoplasmic reticulum (SR) or endoplasmic reticulum (ER) is crucial for muscle contraction, cell growth, apoptosis, learning and memory. TRIC channels are cation channels balancing the SR and ER membrane potentials, implicated in Ca2+ signaling and homeostasis. Kasuya et al. 2016 presented crystal structures of two prokaryotic TRIC channels in the closed state and conducted structure-based functional analyses of them. Each trimer subunit consists of seven TMSs with two inverted 3 TMS repeats (Silverio and Saier 2011). The electrophysiological, biochemical and biophysical analyses revealed that TRIC channels possess an ion-conducting pore within each subunit, and that trimer formation contributes to the stability of the protein. The symmetrically related TMS2 and TMS5 helices are kinked at conserved glycine clusters, and these kinks are important for channel activity. The kinks in TMS2 and TMS5 generate lateral fenestrations at each subunit interface that are occupied by lipid molecules (Kasuya et al. 2016). 

Su et al. 2017 described the structures of two prokaryotic homologues, archaeal SaTRIC from Sulfolobus acidocaldarius and bacterial CpTRIC from Colwellia psychrerythraea, showing that TRIC channels are symmetrical trimers with transmembrane pores through each protomer. Each pore holds a string of water molecules centred at kinked helices in two inverted-repeat triple-helix bundles (THBs). The pores are locked in a closed state by a hydrogen bond network at the C-terminus of the THBs, which is lost when the pores assume an open conformation. The transition between the open and closed states seems to be mediated by cation binding to conserved residues along the three-fold axis. Electrophysiology and mutagenesis studies showed that prokaryotic TRICs have similar functional properties to those of mammalian TRICs and implicate the three-fold axis in the allosteric regulation of the channel.  SaTRIC appears to be a Cl- channel (Su et al. 2017).

The transport reaction catalyzed by eukaryotic TRIC channels is:

Cation (PK/PNa =1.5; intracellular stores) Cations (cytoplasm)

The transport reaction catalyzed by the prokaryotic TRIC channels/carriers may be:

Anion(s) (out) ⇌ Anion(s) (in)

References associated with 1.A.62 family:

Cabral, W.A., M. Ishikawa, M. Garten, E.N. Makareeva, B.M. Sargent, M. Weis, A.M. Barnes, E.A. Webb, N.J. Shaw, L. Ala-Kokko, F.L. Lacbawan, W. Högler, S. Leikin, P.S. Blank, J. Zimmerberg, D.R. Eyre, Y. Yamada, and J.C. Marini. (2016). Absence of the ER Cation Channel TMEM38B/TRIC-B Disrupts Intracellular Calcium Homeostasis and Dysregulates Collagen Synthesis in Recessive Osteogenesis Imperfecta. PLoS Genet 12: e1006156. 27441836
Kasuya, G., M. Hiraizumi, A.D. Maturana, K. Kumazaki, Y. Fujiwara, K. Liu, Y. Nakada-Nakura, S. Iwata, K. Tsukada, T. Komori, S. Uemura, Y. Goto, T. Nakane, M. Takemoto, H.E. Kato, K. Yamashita, M. Wada, K. Ito, R. Ishitani, M. Hattori, and O. Nureki. (2016). Crystal structures of the TRIC trimeric intracellular cation channel orthologues. Cell Res 26: 1288-1301. 27909292
Lv, F., X.J. Xu, J.Y. Wang, Y. Liu, Asan, J.W. Wang, L.J. Song, Y.W. Song, Y. Jiang, O. Wang, W.B. Xia, X.P. Xing, and M. Li. (2016). Two novel mutations in TMEM38B result in rare autosomal recessive osteogenesis imperfecta. J Hum Genet. [Epub: Ahead of Print] 26911354
Matyjaszkiewicz, A., E. Venturi, F. O''Brien, T. Iida, M. Nishi, H. Takeshima, K. Tsaneva-Atanasova, and R. Sitsapesan. (2015). Subconductance gating and voltage sensitivity of sarcoplasmic reticulum K+ channels: a modeling approach. Biophys. J. 109: 265-276. 26200862
Ou, X., J. Guo, L. Wang, H. Yang, X. Liu, J. Sun, and Z. Liu. (2017). Ion- and water-binding sites inside an occluded hourglass pore of a trimeric intracellular cation (TRIC) channel. BMC Biol 15: 31. 28431535
Shin, S.K., H.S. Park, H.J. Kwon, H.J. Yoon, and J.W. Suh. (2007). Genetic characterization of two S-adenosylmethionine-induced ABC transporters reveals their roles in modulations of secondary metabolism and sporulation in Streptomyces coelicolor M145. J Microbiol Biotechnol 17: 1818-1825. 18092466
Silverio, A.L. and M.H. Saier, Jr. (2011). Bioinformatic characterization of the trimeric intracellular cation-specific channel protein family. J. Membr. Biol. 241: 77-101. 21519847
Su, M., F. Gao, Q. Yuan, Y. Mao, D.L. Li, Y. Guo, C. Yang, X.H. Wang, R. Bruni, B. Kloss, H. Zhao, Y. Zeng, F.B. Zhang, A.R. Marks, W.A. Hendrickson, and Y.H. Chen. (2017). Structural basis for conductance through TRIC cation channels. Nat Commun 8: 15103. 28524849
Yang, H., M. Hu, J. Guo, X. Ou, T. Cai, and Z. Liu. (2016). Pore architecture of TRIC channels and insights into their gating mechanism. Nature. [Epub: Ahead of Print] 27698420
Yazawa M., C. Ferrante, J. Feng, K. Mio, T. Ogura, M. Zhang, P. Lin, Z. Pan, S. Komazaki, K. Kato, M. Nishi, X. Zhao, N. Weisleder, C. Sato., J. Ma and H. Takeshima. (2007). TRIC channels are essential for Ca2+ handling in intracellular stores. Nature. 448:78-82. 17611541