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 , encoded by the transmembrane protein 38A (TMEM38A) gene . It is one of two known TRIC proteins , the other being TRIC-B .
Structure
TRIC-A is a 33kDa transmembrane protein , expressed predominantly in excitable tissues including skeletal muscle and brain . Its N-terminal region is located in the SR lumen or within the nucleus while its C-terminal region projects into the cytoplasm . 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).
Function
TRIC-A is permeable to both Na and K but not divalent cations like Ca . 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 Ca release; as such, K flux into the SR through TRIC-A is thought to support RyR1-mediated efflux of Ca 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
TRIC-A has been implicated in the regulation of arterial blood pressure through regulating the excitability of vascular smooth muscle cells. 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. 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 (see personalized medicine ).
See also
References
^ GRCh38: Ensembl release 89: ENSG00000072954 – Ensembl , May 2017
^ 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 .^ 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 .
^ 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 .
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