Trimeric intracellular cation channels and sarcoplasmic/endoplasmic reticulum calcium homeostasis.
Trimeric intracellular cation channels and sarcoplasmic/endoplasmic reticulum calcium homeostasis.
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DOI：
10.1161/circresaha.114.301816
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发表时间：
2014-02-14
影响因子：
20.1
通讯作者：
Ma J
中科院分区：
文献类型：
--
作者：
Zhou X;Lin P;Yamazaki D;Park KH;Komazaki S;Chen SR;Takeshima H;Ma J
TRIC代表了一类新的三聚体细胞内阳离子通道。在人类和小鼠基因组中已经鉴定出两种TRIC亚型：trici - a亚型主要表达于肌肉细胞的肌浆网（SR），而trici - b亚型普遍表达于所有组织的内质网（ER）。TRIC- a或TRIC- b的基因消融导致SR/ER膜上K+渗透和Ca2+释放受损，支持TRIC通道提供平衡K+通量的假设，减少SR/ER膜去极化，维持驱动SR/ER Ca2+释放的电化学梯度。特里克- a和特里克- b似乎在可兴奋和不可兴奋细胞的Ca2+信号传导中具有不同的功能。trica - / -小鼠在动脉平滑肌中显示有缺陷的Ca2+火花和自发的瞬时外向电流，并发展为高血压，以及骨骼肌功能障碍。敲除tricc - b导致气道上皮细胞IP3受体介导的Ca2+释放异常，呼吸缺陷和新生儿死亡。缺少TRIC-A和TRIC-B的双敲除小鼠由于心脏骤停表现出胚胎致命性。这种加重的致死率表明，在胚胎心肌细胞中，trica和tricc - b在Ca2+信号传导中具有互补的生理功能。trici -a−/−trici -b+/−小鼠存活且易发生应激性心力衰竭。最近的证据表明，trica直接调节心脏ryanodine受体（RyR2） Ca2+释放通道的功能，这反过来控制存储过载诱导的SR Ca2+释放。因此，TRIC通道除了为SR/ER Ca2+释放提供逆流外，还可以作为直接调节RyR/IP3受体通道功能的辅助蛋白。
TRIC represents a novel class of trimeric intracellular cation channels. Two TRIC isoforms have been identified in both the human and mouse genomes: TRIC-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 Ca2+ 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 Ca2+ release. TRIC-A and TRIC-B appear to have differential functions in Ca2+ signaling in excitable and non-excitable cells. Tric-a−/− mice display defective Ca2+ 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 Ca2+ release in airway epithelial cells, respiratory defects and neonatal lethality. Double-knockout mice lacking both TRIC-A and TRIC-B show embryonic lethality due to cardiac arrest. Such an aggravated lethality indicates that TRIC-A and TRIC-B share complementary physiological functions in Ca2+ signaling in embryonic cardiomyocytes. Tric-a−/−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 (RyR2) Ca2+ release channel, which in turn controls store-overload induced Ca2+ release from the SR. Thus, the TRIC channels, in addition to providing a counter-current for SR/ER Ca2+ release, may also function as accessory proteins that directly modulate the RyR/IP3 receptor channel functions.