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首页> 外文期刊>American Journal of Physiology >Insulin causes renal dopamine D1 receptor desensitization via GRK2-mediated receptor phosphorylation involving phosphatidylinositol 3-kinase and protein kinase C.
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Insulin causes renal dopamine D1 receptor desensitization via GRK2-mediated receptor phosphorylation involving phosphatidylinositol 3-kinase and protein kinase C.

机译：胰岛素通过涉及磷脂酰肌醇3激酶和蛋白激酶C的GRK2介导的受体磷酸化作用导致肾多巴胺D1受体脱敏。

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The renal dopamine system plays an important role in sodium homeostasis and a defect in dopamine D1 receptor (D1R) function is present in hypertension, diabetes, and aging. Our previous studies in hyperinsulinemic animals and in renal cell cultures treated with insulin showed decrease in D1R number and defective coupling to G proteins; however, the exact mechanisms remained unknown. Therefore, we investigated insulin-mediated D1R desensitization and underlying molecular mechanism in opossum kidney (OK) cells. Chronic exposure (24 h) of OK cells to 10 nM insulin caused significant decrease in D1R number and agonist affinity. The D1R was hyperserine phosphorylated, uncoupled from G proteins and SKF38393, a D1R agonist, failed to stimulate G proteins and inhibit Na-K-ATPase activity. Insulin increased protein kinase C (PKC) activity and caused G protein-coupled receptor kinase 2 (GRK2) translocation to the membranes. Tyrosine kinase inhibitor genistein and phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin blocked insulin-mediated PKC activation and GRK2 membranous translocation. In addition to genistein and wortmannin, GRK2 membranous tranlocation was also blocked by PKC inhibitor chelerythrine chloride and GRK2-specific siRNA. Genistein, wortmannin, chelerythrine chloride, and GRK2 siRNA abrogated D1R serine phosphorylation and normalized D1R expression and affinity in insulin-treated cells. Furthermore, these inhibitors and siRNA restored D1R G protein coupling and ability of SKF38393 to inhibit Na-K-ATPase activity. In conclusion, insulin-induced D1R desensitization involves PI3K, PKC, and GRK2. Insulin activates PI3K-PKC-GRK2 cascade, causing D1R serine phosphorylation, which leads to D1R downregulation and uncoupling from G proteins, and results in the failure of SKF38393 to stimulate G proteins and inhibit Na-K-ATPase activity.
机译：肾脏多巴胺系统在钠稳态中起着重要作用，而多巴胺D1受体（D1R）功能的缺陷在高血压，糖尿病和衰老中存在。我们先前在高胰岛素血症动物和用胰岛素治疗的肾细胞培养物中的研究表明，D1R数量减少且与G蛋白的结合不良。但是，确切的机制仍然未知。因此，我们调查了负鼠肾（OK）细胞中胰岛素介导的D1R脱敏和潜在的分子机制。 OK细胞长期暴露于10 nM胰岛素中（24 h）导致D1R数量和激动剂亲和力显着下降。 D1R被丝氨酸磷酸化，与G蛋白脱钩，而D1R激动剂SKF38393无法刺激G蛋白并抑制Na-K-ATPase活性。胰岛素增加了蛋白激酶C（PKC）的活性，并导致G蛋白偶联受体激酶2（GRK2）易位至膜。酪氨酸激酶抑制剂染料木黄酮和磷脂酰肌醇3-激酶（PI3K）抑制剂渥曼青霉素可阻断胰岛素介导的PKC活化和GRK2膜移位。除金雀异黄素和渥曼青霉素外，PKC抑制剂白屈菜红碱氯化物和GRK2特异性siRNA还阻止了GRK2膜的易位。 Genistein，渥曼青霉素，氯化白屈菜红碱和GRK2 siRNA消除了D1R丝氨酸磷酸化，并在胰岛素处理的细胞中使D1R表达和亲和力正常化。此外，这些抑制剂和siRNA恢复了D1R G蛋白的偶联以及SKF38393抑制Na-K-ATPase活性的能力。总之，胰岛素诱导的D1R脱敏涉及PI3K，PKC和GRK2。胰岛素激活PI3K-PKC-GRK2级联，导致D1R丝氨酸磷酸化，从而导致D1R下调和与G蛋白解偶联，并导致SKF38393无法刺激G蛋白和抑制Na-K-ATPase活性。

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