Other
12 Authors
- Lin PH,
- Park KH,
- Zou X,
- Ma Z,
- Zhou X,
- Murayama T,
- Yamazaki D,
- Takeshima H,
- Ma J,
- Zhou J,
- Nishi M,
- Qiu L
| First Author | Zhou X | Year | 2020 |
| Journal | Circ Res | Volume | 126 |
| Issue | 4 | Pages | 417-435 |
| PubMed ID | 31805819 | Mgi Jnum | J:302824 |
| Mgi Id | MGI:6510217 | Doi | 10.1161/CIRCRESAHA.119.316241 |
| Citation | Zhou X, et al. (2020) TRIC-A Channel Maintains Store Calcium Handling by Interacting With Type 2 Ryanodine Receptor in Cardiac Muscle. Circ Res 126(4):417-435 |
| abstractText | RATIONALE: Trimeric intracellular cation (TRIC)-A and B are distributed to endoplasmic reticulum/sarcoplasmic reticulum intracellular Ca(2+) stores. The crystal structure of TRIC has been determined, confirming the homotrimeric structure of a potassium channel. While the pore architectures of TRIC-A and TRIC-B are conserved, the carboxyl-terminal tail (CTT) domains of TRIC-A and TRIC-B are different from each other. Aside from its recognized role as a counterion channel that participates in excitation-contraction coupling of striated muscles, the physiological function of TRIC-A in heart physiology and disease has remained largely unexplored. OBJECTIVE: In cardiomyocytes, spontaneous Ca(2+) waves, triggered by store overload-induced Ca(2+) release mediated by the RyR2 (type 2 ryanodine receptor), develop extrasystolic contractions often associated with arrhythmic events. Here, we test the hypothesis that TRIC-A is a physiological component of RyR2-mediated Ca(2+) release machinery that directly modulates store overload-induced Ca(2+) release activity via CTT. METHODS AND RESULTS: We show that cardiomyocytes derived from the TRIC-A(-/-) (TRIC-A knockout) mice display dysregulated Ca(2+) movement across sarcoplasmic reticulum. Biochemical studies demonstrate a direct interaction between CTT-A and RyR2. Modeling and docking studies reveal potential sites on RyR2 that show differential interactions with CTT-A and CTT-B. In HEK293 (human embryonic kidney) cells with stable expression of RyR2, transient expression of TRIC-A, but not TRIC-B, leads to apparent suppression of spontaneous Ca(2+) oscillations. Ca(2+) measurements using the cytosolic indicator Fura-2 and the endoplasmic reticulum luminal store indicator D1ER suggest that TRIC-A enhances Ca(2+) leak across the endoplasmic reticulum by directly targeting RyR2 to modulate store overload-induced Ca(2+) release. Moreover, synthetic CTT-A peptide facilitates RyR2 activity in lipid bilayer reconstitution system, enhances Ca(2+) sparks in permeabilized TRIC-A(-/-) cardiomyocytes, and induces intracellular Ca(2+) release after microinjection into isolated cardiomyocytes, whereas such effects were not observed with the CTT-B peptide. In response to isoproterenol stimulation, the TRIC-A(-/-) mice display irregular ECG and develop more fibrosis than the WT (wild type) littermates. CONCLUSIONS: In addition to the ion-conducting function, TRIC-A functions as an accessory protein of RyR2 to modulate sarcoplasmic reticulum Ca(2+) handling in cardiac muscle. |
