Angiotensin II-induced down-regulation of inositol trisphosphate receptors in WB rat liver epithelial cells - Evidence for involvement of the proteasome pathway
Angiotensin II-induced down-regulation of inositol trisphosphate receptors in WB rat liver epithelial cells - Evidence for involvement of the proteasome pathway
复制标题
DOI：
10.1074/jbc.272.19.12454
复制
发表时间：
1997-05-09
影响因子：
4.8
通讯作者：
Joseph, SK
中科院分区：
文献类型：
--
作者：
Bokkala, S;Joseph, SK
血管紧张素II(Ang II)对WB大鼠肝上皮细胞的慢性刺激可引起I型和III型肌醇1，4，5-三磷酸受体(IP(3)Rs)下调，血管加压素、缓激肽、表皮生长因子或12-O-十四酰佛波醇-13-乙酸酯对此无影响。血管紧张素转换酶II诱导的IP(3)Rs下调可在2 h内检测到，并可抑制IP3诱导的细胞内钙释放，IP3R下调是可逆的，IP(3)Rs的同源和异源低聚物对Ang II诱导的降解同样敏感。氯喹和NH4Cl使IP(3)Rs的基础水平增加一倍，提示IP(3)Rs的基础周转是通过溶酶体途径发生的，而Ang II诱导的IP(3)Rs的降解不受这些抑制剂的影响，这表明IP(3)Rs的刺激降解是通过非溶酶体途径发生的，半胱氨酸蛋白酶和蛋白酶体抑制剂N-乙酰-亮氨酸-去亮氨酸完全阻止Ang II介导的IP(3)受体的下调，而结构类似的N-乙酰-亮氨酸-蛋氨酸则不起作用，而高度特异的蛋白酶体抑制剂Lactakystin也阻断了Ang II介导的IP3R降解，Ang II刺激增加了抗泛素抗体诱导的LP3R免疫沉淀量，我们认为Ang II刺激的IP3R降解涉及蛋白质泛素化的增强和蛋白酶体途径的降解。
Chronic stimulation of WB rat liver epithelial cells by angiotensin II (Ang II) resulted in the down-regulation of both type I and type III myo-inositol 1,4,5-trisphosphate receptors (IP(3)Rs), Stimulation with vasopressin, bradykinin, epidermal growth factor, or 12-O-tetradecanoylphorbol-13-acetate was without effect. Ang II-induced down-regulation of IP(3)Rs could be detected within 2 h and resulted in an inhibition of IP3-induced Ca2+ release from permeabilized cells, IP3R down-regulation was reversible, and both home- and heterooligomers of IP(3)Rs were equally susceptible to Ang II-induced degradation. Chloroquine and NH4Cl increased the basal levels of IP(3)Rs by a-fold, suggesting that the basal turnover of IP(3)Rs occurs via a lysosomal pathway, However, Ang II-induced degradation of IP3R was not affected by these inhibitors, suggesting that stimulated degradation of IP(3)Rs occurs via a non-lysosomal pathway, The cysteine protease and proteasomal inhibitor N-acetyl-Leu-Leu-norleucinal completely prevented Ang II-mediated down-regulation of IP(3)Rs, whereas the structural analog N-acetyl-Leu-Leu-methioninal was without effect, Lactacystin, a highly specific proteasome inhibitor, also blocked Ang II-mediated IP3R degradation, Stimulation with Ang II increased the amount of LP3R immunoprecipitated by anti-ubiquitin antibodies, We conclude that Ang II-stimulated IP3R degradation involves enhanced ubiquitination of the protein and degradation by the proteasome pathway.