de Frutos Sergio, Saura Marta, Rivero-Vilches Francisco J, Rodriguez-Puyol D, Rodriguez-Puyol M
Department of Physiology, Alcalá de Henares University, Madrid, Spain.
Biochim Biophys Acta. 2003 Dec 7;1643(1-3):105-12. doi: 10.1016/j.bbamcr.2003.10.003.
Natriuretic peptides (NP) activate particulate guanylate cyclase (pGC) and nitric oxide (NO) activates soluble guanylate cyclase (sGC). Both guanylate cyclases catalyse the formation of the same second messenger, cyclic guanosine 3',5'-monophosphate (cGMP), which activates the cGMP-dependent protein kinases (PKG). PKG then starts a signalling cascade that mediates many cardiovascular and renal effects, such as smooth muscle relaxation and diuresis. Many cell types possess both sGC and pGC. Because both GC-cGMP systems play complementary roles, an interaction between the two pathways might represent an important physiological control mechanism. In this report we demonstrate an interaction between the two pathways. C-type natriuretic peptide (CNP) decreased the beta-subunit of sGC (sGC-beta) steady-state protein levels and enzymatic activity in cultured human mesangial cells (HMC) in a time- and dose-dependent manner. This down-regulation was not dependent on changes in sGC-beta mRNA levels. Treatment of the cells with the stable cGMP analogue 8-Br-cGMP or the phosphodiesterase type-5 inhibitor Zaprinast produced the same down-regulatory effect. Inhibition of PKG or proteasome activity prevented the CNP-induced reduction of sGC-beta protein levels and activity. Taken together, these results demonstrate that pGC activation induces a post-transductional down-regulation of sGC by a mechanism involving PKG and the proteasome pathway.
利钠肽（NP）激活颗粒型鸟苷酸环化酶（pGC），而一氧化氮（NO）激活可溶性鸟苷酸环化酶（sGC）。两种鸟苷酸环化酶都催化形成相同的第二信使，即环鸟苷酸3',5'-单磷酸（cGMP），cGMP进而激活依赖cGMP的蛋白激酶（PKG）。PKG随后启动一个信号级联反应，介导许多心血管和肾脏效应，如平滑肌舒张和利尿作用。许多细胞类型同时拥有sGC和pGC。由于两种GC-cGMP系统发挥互补作用，两条信号通路之间的相互作用可能代表一种重要的生理控制机制。在本报告中，我们证明了两条信号通路之间的相互作用。C型利钠肽（CNP）在培养的人肾小球系膜细胞（HMC）中，以时间和剂量依赖性方式降低了sGC的β亚基（sGC-β）的稳态蛋白水平和酶活性。这种下调不依赖于sGC-β mRNA水平的变化。用稳定的cGMP类似物8-溴-cGMP或5型磷酸二酯酶抑制剂扎普司特处理细胞，产生了相同的下调效应。抑制PKG或蛋白酶体活性可阻止CNP诱导的sGC-β蛋白水平和活性的降低。综上所述，这些结果表明，pGC激活通过一种涉及PKG和蛋白酶体途径的机制，诱导sGC发生转导后下调。
