Phosphorylation-regulated endoplasmic reticulum retention signal in the renal outer-medullary K+ channel (ROMK).
Phosphorylation-regulated endoplasmic reticulum retention signal in the renal outer-medullary K+ channel (ROMK).
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DOI：
10.1073/pnas.0504332102
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发表时间：
2005-07
影响因子：
11.1
通讯作者：
A. O'Connell;Q. Leng;K. Dong;G. MacGregor;G. Giebisch;S. Hebert
中科院分区：
文献类型：
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作者：
A. O'Connell;Q. Leng;K. Dong;G. MacGregor;G. Giebisch;S. Hebert
肾脏外髓K+通道(ROMK；Kir1.1)调节肾脏哺乳动物肾单位K+的分泌，这对钠和钾的动态平衡都是至关重要的。ROMK在细胞质膜上的转录后表达受蛋白质从内质网(ER)向细胞表面的传递和笼蛋白包裹的凹坑中依赖于动力蛋白的内吞机制的恢复的调节。在ROMK1的NH(2)端的S44可以被PKA和血清和糖皮质激素诱导的激酶-1磷酸化，这一过程增加了功能通道的表面表达。我们提供的证据表明，S44的磷酸化通过增加其细胞表面递送来调节通道表达，从而抑制COOH末端的ER保留信号。这种ER保留信号的磷酸化开关可以提供一组成熟的、适当折叠的通道，以便快速传递到质膜。内向整流K~+通道的X射线晶体结构表明，在通道同分异构体中，NH(2)末端与相邻亚基的远端COOH末端紧密对接，这对通道选通很重要。因此，NH(2)末端的磷酸化修饰ROMK1中COOH末端的ER保留信号可以作为正确的亚基折叠的检查点，而亚基折叠对通道门控至关重要。
The renal outer-medullary K+ channel (ROMK; Kir1.1) mediates K+ secretion in the renal mammalian nephron that is critical to both sodium and potassium homeostasis. The posttranscriptional expression of ROMK in the plasma membrane of cells is regulated by delivery of protein from endoplasmic reticulum (ER) to the cell surface and by retrieval by dynamin-dependent endocytic mechanisms in clathrin-coated pits. The S44 in the NH(2) terminus of ROMK1 can be phosphorylated by PKA and serum- and glucocorticoid-inducible kinase-1, and this process increases surface expression of functional channels. We present evidence that phosphorylation of S44 modulates channel expression by increasing its cell surface delivery consequent to suppression of a COOH-terminal ER retention signal. This phosphorylation switch of the ER retention signal could provide a pool of mature and properly folded channels for rapid delivery to the plasma membrane. The x-ray crystal structures of inward rectifier K+ channels have shown a close apposition of the NH(2) terminus with the distal COOH terminus of the adjacent subunit in the channel homotetramer, which is important to channel gating. Thus, NH(2)-terminal phosphorylation modifying a COOH-terminal ER retention signal in ROMK1 could serve as a checkpoint for proper subunit folding critical to channel gating.