Dual regulation of the parathyroid hormone (PTH)/PTH-related peptide receptor signaling by protein kinase C and β-arrestins
Dual regulation of the parathyroid hormone (PTH)/PTH-related peptide receptor signaling by protein kinase C and β-arrestins
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DOI：
10.1210/en.2002-220232
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发表时间：
2002-10-01
期刊：
影响因子：
4.8
通讯作者：
Lohse, MJ
中科院分区：
文献类型：
--
作者：
Castro, M;Dicker, F;Lohse, MJ
我们在这里研究了第二信使依赖性激酶和β-抑制蛋白在PTH受体（PTHR）信号传导的短期调节中的作用。在瞬时表达PTHR的COS-7细胞中抑制蛋白激酶C（PKC），导致PTH刺激的磷酸肌醇（IP）和cAMP产生增加约2倍。蛋白激酶A的抑制使cAMP产生增加1.5倍而不影响IP信号传导。PKC抑制对PTHR介导的G（q）信号传导的影响对于磷酸化缺陷的羧基末端截短的PTHR（T480）强烈降低。PKC抑制与激动剂刺激的PTHR磷酸化和内化减少相关，而不阻断PTH依赖性β-arrestin 2向质膜的动员。β-抑制蛋白的过表达强烈降低了PTHR介导的IP信号，而cAMP的产生被削弱到a。低得多的程度。PTH刺激信号的调节β-arrestins受损的截短T480 receptor.我们的数据揭示的机制，和远端，受体调节PTHR介导的信号通路的第二信使依赖性激酶。我们的结论是，调节PTHR介导的信号转导的PKC和β-arrestins是可分离的现象，都涉及羧基末端的受体。PKC和β-arrestins在PTHR介导的G（q）信号通过受体水平的独立机制优先调节中的主要作用已经确立。
We examined here the role of second messenger-dependent kinases and beta-arrestins in short-term regulation of the PTH receptor (PTHR) signaling. The inhibition of protein kinase C, (PKC) in COS-7 cells transiently expressing PTHR, led to an approximately 2-fold increase in PTH-stimulated inositol phosphate (IP) and cAMP production. The inhibition of protein kinase A increased cAMP production 1.5-fold without affecting IP signaling. The effects of PKC inhibition on PTHR-mediated G(q) signaling were strongly decreased for a carboxy-terminally truncated PTHR (T480) that is phosphorylation deficient. PKC inhibition was associated with a decrease in agonist-stimulated PTHR phosphorylation and internalization without blocking PTH-dependent mobilization of beta-arrestin2 to the plasma membrane. Overexpression of beta-arrestins strongly decreased the PTHR-mediated IP signal, whereas cAMP production was impaired to a. much lower extent. The regulation of PTH-stimulated signals by beta-arrestins was impaired for the truncated T480 receptor.Our data reveal mechanisms at, and distal to, the receptor regulating PTHR-mediated signaling pathways by second messenger-dependent kinases. We conclude that regulation of PTHR-mediated signaling by PKC and beta-arrestins are separable phenomena that both involve the carboxy terminus of the receptor. A major role for PKC and beta-arrestins in preferential regulation of PTHR-mediated G(q) signaling by independent mechanisms at the receptor level was established.