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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >PKC-dependent coupling of calcium permeation through transient receptor potential canonical 3 (TRPC3) to calcineurin signaling in HL-1 myocytes
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PKC-dependent coupling of calcium permeation through transient receptor potential canonical 3 (TRPC3) to calcineurin signaling in HL-1 myocytes

机译：PKC依赖的钙渗透通过瞬时受体电位规范3（TRPC3）与钙调神经磷酸信号在HL-1心肌细胞中的偶联

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摘要

Cardiac transient receptor potential canonical (TRPC) channels are crucial upstream components of Ca~(2+)/calcineurinuclear factor of activated T cells (NFAT) signaling, thereby controlling cardiac tran-scriptional programs. The linkage between TRPC-mediated Ca~(2+) signals and NFAT activity is still incompletely understood. TRPC conductances may govern calcineurin activity and NFAT transloca-tion by supplying Ca~(2+) either directly through the TRPC pore into a regulatory microdomain or indirectly via promotion of voltage-dependent Ca~(2+) entry. Here, we show that a point mutation in the TRPC3 selectivity filter (E630Q), which disrupts Ca~(2+) permeability but preserves monovalent permeation, abrogates agonist-induced NFAT signaling in HEK293 cells as well as in murine HL-1 atrial myocytes. The E630Q mutation fully retains the ability to convert phos-pholipase C-linked stimuli into L-type (Cav1.2) channel-mediated Ca~(2+) entry in HL-1 cells, thereby generating a dihydropyridine-sensitive Ca~(2+) signal that is isolated from the NFAT pathway. Prevention of PKC-dependent modulation of TRPC3 by either inhibition of cellular kinase activity or mutation of a critical phosphorylation site in TRPC3 (T573A), which disrupts targeting of calcineurin into the channel complex, converts cardiac TRPC3-mediated Ca~(2+) signaling into a transcriptionally silent mode. Thus, we demonstrate a dichotomy of TRPC-mediated Ca~(2+) signaling in the heart constituting two distinct pathways that are differentially linked to gene transcription. Coupling of TRPC3 activity to NFAT translocation requires microdomain Ca~(2+) signaling by PKC-modified TRPC3 complexes. Our results identify TRPC3 as a pivotal signaling gateway in Ca~(2+-) dependent control of cardiac gene expression.
机译：心脏瞬态受体潜在规范（TRPC）通道是Ca〜（2 +）/钙调神经磷酸酶/激活的T细胞（NFAT）信号的核因子的关键上游成分，从而控制心脏转录程序。 TRPC介导的Ca〜（2+）信号与NFAT活性之间的联系仍不完全清楚。 TRPC电导可通过直接通过TRPC孔将Ca〜（2+）供应到调节微区中或间接地通过促进电压依赖性Ca〜（2+）进入来间接控制钙调神经磷酸酶活性和NFAT易位。在这里，我们发现TRPC3选择性过滤器（E630Q）中的点突变可破坏Ca〜（2+）的通透性，但保留单价渗透，可消除HEK293细胞和鼠类HL-1心房肌细胞中激动剂诱导的NFAT信号传导。 。 E630Q突变完全保留了将磷脂酶C连接的刺激转化为HL-1细胞中L型（Cav1.2）通道介导的Ca〜（2+）进入的能力，从而产生了对二氢吡啶敏感的Ca〜（从NFAT途径分离的2+）信号。通过抑制细胞激酶活性或TRPC3（T573A）中关键磷酸化位点的突变来防止TRPC3的PKC依赖性调节，从而将钙调神经磷酸酶的靶向性破坏到通道复合体中，从而转换心脏TRPC3介导的Ca〜（2+）信号传导进入转录静音模式。因此，我们证明了在心脏中由TRPC介导的Ca〜（2+）信号二分法构成了两个不同的途径，这些途径与基因转录差异连接。 TRPC3活性与NFAT易位的耦合需要PKC修饰的TRPC3复合物的微域Ca〜（2+）信号传导。我们的结果确定TRPC3是心脏基因表达的Ca〜（2 +-）依赖性控制中的关键信号通路。

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