Function and Regulation of Endothelin Type A Receptor-Operated Transient Receptor Potential Canonical Channels
Function and Regulation of Endothelin Type A Receptor-Operated Transient Receptor Potential Canonical Channels
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DOI：
10.1254/jphs.11162fp
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发表时间：
2011-12-01
影响因子：
3.5
通讯作者：
Miwa, Soichi
中科院分区：
文献类型：
--
作者：
Horinouchi, Takahiro;Terada, Koji;Miwa, Soichi
本研究的目的是确定由内皮素A型受体(ETAR)激活所触发的受体操控的钙内流(ROCE)的瞬时受体潜能型(TRPC)通道，并阐明TRPC通道C端的钙调蛋白(CaM)/肌醇I，4，5-三磷酸(IP3)受体结合(CIRB)结构域在ETAR激活的通道调节中的重要性。在共表达ETAR和七种TRPC亚型之一的HEK293细胞中，ETAR刺激通过TRPC3、TRPC5、TRPC6和TRPC7诱导ROCE。G(Q)蛋白、磷脂酶C(PLC)和CaM的选择性抑制剂可抑制TRPC3和TRPC6介导的ROCE。TRPC3和TRPC6的CIRB结构域缺失突变体不能诱导Etar介导的ROCE。CIRB结构域的缺失或CaM的药物抑制都不能抑制这些通道对质膜的靶向性。这些结果表明：1)TRPC3、TRPC5、TRPC6和TRPC7可以作为Etar操纵的钙通道；2)G(Q)蛋白、PLC和CaM参与了TRPC3和TRPC6介导的ROCE；3)ETAR介导的TRPC3和TRPC6的激活需要CIRB结构域；4)通过CIRB结构域的缺失和CaM的抑制取消了Etar诱导的ROCE，这是由于CaM与通道结合的丧失，而不是细胞表面TRPC3和TRPC6的丢失。[补充数字：仅在http://dx.doi.org/10.1254/jphs.11162FP]上提供
The purpose of this study is to identify transient receptor potential canonical (TRPC) channels responsible for receptor-operated Ca2+ entry (ROCE) triggered by activation of endothelin type A receptor (ETAR) and to clarify the importance of calmodulin (CaM)/inositol I,4,5-trisphosphate (IP3) receptor binding (CIRB) domain at the C terminus of TRPC channels in ETAR-activated channel regulation. In HEK293 cells coexpressing ETAR and one of seven TRPC isoforms, ETAR stimulation induced ROCE through TRPC3, TRPC5, TRPC6, and TRPC7. The TRPC3- and TRPC6-mediated ROCE was inhibited by selective inhibitors of G(q) protein, phospholipase C (PLC), and CaM. The CIRB domain deletion mutants of TRPC3 and TRPC6 failed to induce ETAR-mediated ROCE. Either deletion of the CIRB domain or pharmacological inhibition of CaM did not inhibit the targeting of these channels to the plasma membrane. These results suggest that 1) TRPC3, TRPC5, TRPC6, and TRPC7 can function as ETAR-operated Ca2+ channels; 2) G(q) protein, PLC, and CaM are involved in TRPC3- and TRPC6-mediated ROCE; 3) ETAR-mediated activation of TRPC3 and TRPC6 requires the CIRB domain; and 4) abolition of ETAR-induced ROCE by CIRB domain deletion and CaM inhibition is due to loss of CaM binding to the channels but not loss of cell surface TRPC3 and TRPC6. [Supplementary Figures: available only at http://dx.doi.org/10.1254/jphs.11162FP]