Trimeric intracellular cation-selective channel A (TRIC-A) is a monovalent cation channel in the SR and nuclear membranes of skeletal muscle cells,[1] [2] 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[3] 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).
TRIC-A is permeable to both Na+ and K+ but not divalent cations like Ca2+. 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; 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.
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.[4] 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).