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Monovalent cation channel
Trimeric intracellular cation-selective channel A (TRIC-A) is a monovalent cation channel in the SR and nuclear membranes of skeletal muscle cells,[5][6] encoded by the transmembrane protein 38A (TMEM38A) gene. It is one of two known TRIC proteins, the other being TRIC-B.
TRIC-A is a 33kDa[7] transmembrane protein, expressed predominantly in excitable tissues including skeletal muscle and brain.[5] Its N-terminal region is located in the SR lumen[7] or within the nucleus while its C-terminal region projects into the cytoplasm.[5] In situ, TRIC-A forms homo-trimers, producing its "bullet-shaped" three-dimensional structure (see Venturi et al. (2012), Figure 1 for a three-dimensional rendering of TRIC-A).
TRIC-A is permeable to both Na+ and K+ but not divalent cations like Ca2+.[5] The channel exhibits marked voltage-dependence, becoming more open when the cytosol is more positively charged than the ER lumen. TMEM38A-knockout mice exhibit reduced Ryanodine receptor 1-mediated Ca2+ release;[5] as such, K+ flux into the SR through TRIC-A is thought to support RyR1-mediated efflux of Ca2+ ions from the sarcoplasmic reticulum into the cytosol. These knockouts also develop hypertension during early adulthood, whereas transgenic mice overexpressing TRIC-A develop hypotension. These results are thought to reflect a role for TRIC-A in the excitability of vascular smooth muscle cells.
Clinical significance
[edit]TRIC-A has been implicated in the regulation of arterial blood pressure through regulating the excitability of vascular smooth muscle cells.[5] Several single-nucleotide polymorphisms (SNPs) in close proximity to the TRIC-A locus increase the risk of hypertension and reduce the efficiency of antihypertensive drugs in its treatment.[8] Such SNPs are in positive linkage disequilibrium with TRIC-A, meaning they are unlikely to be separated by genetic recombination and so are more frequently inherited together from the same parent chromosome. As such, TRIC-A SNPs can provide biomarkers for the diagnosis of essential hypertension and, in future, may help to determine which treatments may be most well-suited to a given individual[5] (see personalized medicine).
- ^ a b c GRCh38: Ensembl release 89: ENSG00000072954 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000031791 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b c d e f g Venturi, Elisa; Sitsapesan, Rebecca; Yamazaki, Daiju; Takeshima, Hiroshi (15 December 2012). "TRIC channels supporting efficient Ca2+ release from intracellular stores". European Journal of Physiology. 465 (2): 187–195. doi:10.1007/s00424-012-1197-5. PMID 23242030. S2CID 14397400.
- ^ Cabral, Wayne A.; Ishikawa, Masaki; Garten, Matthias; Makareeva, Elena N.; Sargent, Brandi M.; Weis, MaryAnn; Barnes, Aileen M.; Webb, Emma A.; Shaw, Nicholas J.; Ala-Kokko, Leena; Lacbawan, Felicitas L.; Högler, Wolfgang; Leikin, Sergey; Blank, Paul S.; Zimmerberg, Joshua; Eyre, David R.; Yamada, Yoshihiko; Marini, Joan C. (21 July 2016). "Absence of the ER Cation Channel TMEM38B/TRIC-B Disrupts Intracellular Calcium Homeostasis and Dysregulates Collagen Synthesis in Recessive Osteogenesis Imperfecta". PLOS Genetics. 12 (7): e1006156. doi:10.1371/journal.pgen.1006156. PMC 4956114. PMID 27441836.
- ^ a b Yazawa, Masayuki; Ferrante, Christopher; Feng, Jue; Mio, Kazuhiro; Ogura, Toshihiko; Zhang, Miao; Lin, Pei-Hui; Pan, Zui; Komazaki, Shinji; Kato, Kazuhiro; Nishi, Miyuki; Zhao, Xiaoli; Weisleder, Noah; Sato, Chikara; Ma, Jianjie; Takeshima, Hiroshi (5 July 2007). "TRIC channels are essential for Ca2+ handling in intracellular stores". Nature. 448 (7149): 78–82. Bibcode:2007Natur.448...78Y. doi:10.1038/nature05928. PMID 17611541. S2CID 4431703.
- ^ Yamazaki, Daiju; Tabara, Yasuharu; Kita, Satomi; Hanada, Hironori; Komazaki, Shinji; Naitou, Daisuke; Mishima, Aya; Nishi, Miyuki; Yamamura, Hisao; Yamamoto, Shinichiro; Kakizawa, Sho; Miyachi, Hitoshi; Yamamoto, Shintaro; Miyata, Toshiyuki; Kawano, Yuhei; Kamide, Kei; Ogihara, Toshio; Hata, Akira; Umemura, Satoshi; Soma, Masayoshi; Takahashi, Norio; Imaizumi, Yuji; Miki, Tetsuro; Iwamoto, Takahiro; Takeshima, Hiroshi (3 August 2011). "TRIC-A Channels in Vascular Smooth Muscle Contribute to Blood Pressure Maintenance". Cell Metabolism. 14 (2): 231–241. doi:10.1016/j.cmet.2011.05.011. hdl:2433/143634. PMID 21803293.
