Parathyroid hormone (PTH) regulates the sodium chloride cotransporter via Ras guanyl releasing protein 1 (Ras-GRP1) and extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein kinase (MAPK) pathway.
Parathyroid hormone (PTH) regulates the sodium chloride cotransporter via Ras guanyl releasing protein 1 (Ras-GRP1) and extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein kinase (MAPK) pathway.
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DOI：
10.1016/j.trsl.2011.07.005
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发表时间：
2011-11
期刊：
影响因子：
--
通讯作者：
Hoover RS
中科院分区：
文献类型：
--
作者：
Ko B;Cooke LL;Hoover RS
氯化钠协同转运蛋白（NCC）是哺乳动物远曲小管（DCT）中主要的盐吸收途径，也是噻嗪类利尿剂的作用部位。利用哺乳动物细胞模型系统，以评估NCC功能，我们以前证明，Ras鸟苷酸释放蛋白1（RasGRP 1）介导佛波酯诱导的抑制NCC的功能和表面表达的PKC-独立和ERK 1/2依赖的方式。鉴于佛波醇酯是DAG的功能类似物，这一发现表明DAG对NCC的潜在生理调节。甲状旁腺激素（PTH）受体是一种G蛋白偶联受体，在DCT中表达并激活PLC，导致DAG的产生。在这里，我们证明了PTH通过PLC/RasGRP 1/ERK通路抑制NCC功能。NCC测量噻嗪敏感性22 Na+通量的功能评估显示，PTH抑制NCC功能。抑制PLC阻止了NCC的抑制，表明PLC是这种效应所必需的。PKC和PKA抑制剂对此抑制没有影响，但MAPK抑制剂完全阻止了PTH的作用。RasGRP 1通过激活小G蛋白Ras来激活MAPK途径。RasGRP 1的基因沉默阻止了PTH介导的NCC活性的抑制、Ras的H-Ras亚型的激活和ERK 1/2 MAPK的激活。这证实了RasGRP 1在通过刺激MAPK途径介导PTH诱导的NCC活性抑制中的关键作用。
The sodium chloride cotransporter (NCC) is the principal salt absorptive pathway in the mammalian distal convoluted tubule (DCT) and is the site of action of thiazide diuretics. Utilizing a mammalian cell model system to assess NCC function we previously demonstrated that Ras Guanyl Releasing Protein 1 (RasGRP1) mediates phorbol ester induced suppression of function and surface expression of NCC in a PKC-independent and ERK1/2 dependent manner. Given that phorbol esters are functional analogues of DAG, this finding suggested a potential physiological regulation of NCC by DAG. The parathyroid hormone (PTH) receptor is a G protein-coupled receptor that is expressed in the DCT and activates PLC resulting in the generation of DAG. Here we demonstrate that PTH suppresses NCC function via a PLC/RasGRP1/ERK pathway. Functional assessment of NCC measuring thiazide-sensitive 22Na+ flux revealed that PTH suppresses NCC function. Inhibition of PLC prevented the suppression of NCC, indicating that PLC was necessary for this effect. Inhibitors of PKC and PKA had no effect on this suppression, but MAPK inhibitors completely prevented the PTH effect. RasGRP1 activates the MAPK pathway though activation of the small G protein Ras. Gene silencing of RasGRP1 prevented the PTH mediated suppression of NCC activity, the activation of the H-Ras isoform of Ras and the activation of ERK1/2 MAPK. This confirmed the critical role of RasGRP1 in mediating the PTH induced suppression of NCC activity through stimulation of the MAPK pathway.
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DOI：
10.1073/pnas.0709506104
发表时间：
2007-12-11
影响因子：
11.1
作者：
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发表时间：
1996-10-01
影响因子：
4.2
作者：
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影响因子：
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作者：
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