Trimeric Intracellular Cation Channels and Sarcoplasmic/Endoplasmic Reticulum Calcium Homeostasis

• Published in: Circulation research 2014-02, Vol.114 (4), p.706-716
• Main Authors: Zhou, Xinyu, Lin, Peihui, Yamazaki, Daiju, Park, Ki Ho, Komazaki, Shinji, Chen, S.R. Wayne, Takeshima, Hiroshi, Ma, Jianjie
• Format: Article
• Language: English
• Subjects: Animals; Calcium - metabolism; Calcium Signaling - physiology; Endoplasmic Reticulum - physiology; Homeostasis - physiology; Humans; Ion Channels - genetics; Ion Channels - metabolism; Mice; Sarcoplasmic Reticulum - physiology
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.114.301816

Trimeric intracellular cation channels (TRIC) represents a novel class of trimeric intracellular cation channels. Two TRIC isoforms have been identified in both the human and the mouse genomesTRIC-A, a subtype predominantly expressed in the sarcoplasmic reticulum (SR) of muscle cells, and TRIC-B, a ubiquitous subtype expressed in the endoplasmic reticulum (ER) of all tissues. Genetic ablation of either TRIC-A or TRIC-B leads to compromised K permeation and Ca release across the SR/ER membrane, supporting the hypothesis that TRIC channels provide a counter balancing K flux that reduces SR/ER membrane depolarization for maintenance of the electrochemical gradient that drives SR/ER Ca release. TRIC-A and TRIC-B seem to have differential functions in Ca signaling in excitable and nonexcitable cells. Tric-a mice display defective Ca sparks and spontaneous transient outward currents in arterial smooth muscle and develop hypertension, in addition to skeletal muscle dysfunction. Knockout of TRIC-B results in abnormal IP3 receptor–mediated Ca release in airway epithelial cells, respiratory defects, and neonatal lethality. Double knockout mice lacking both TRIC-A and TRIC-B show embryonic lethality as a result of cardiac arrest. Such an aggravated lethality indicates that TRIC-A and TRIC-B share complementary physiological functions in Ca signaling in embryonic cardiomyocytes. Tric-a and Tric-b mice are viable and susceptible to stress-induced heart failure. Recent evidence suggests that TRIC-A directly modulates the function of the cardiac ryanodine receptor 2 Ca release channel, which in turn controls store-overload–induced Ca release from the SR. Thus, the TRIC channels, in addition to providing a countercurrent for SR/ER Ca release, may also function as accessory proteins that directly modulate the ryanodine receptor/IP3 receptor channel functions.