Protein kinase C potentiation of the tyrosine kinase inhibitor-stimulated cyclic GMP production in rat pinealocytes.
Protein kinase C potentiation of the tyrosine kinase inhibitor-stimulated cyclic GMP production in rat pinealocytes.
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DOI：
10.1016/s0006-2952(96)00694-6
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发表时间：
1997-01
影响因子：
5.8
通讯作者：
T. Ogiwara;C. Chik;A. Ho
中科院分区：
文献类型：
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作者：
T. Ogiwara;C. Chik;A. Ho
抑制酪氨酸激酶活性可提高大鼠松果体细胞内环鸟苷酸(CGMP)水平。由于蛋白激酶C(PKC)和细胞内钙离子都与激动剂刺激的cGMP积聚相互作用，因此本研究探讨了它们与酪氨酸激酶抑制剂介导的cGMP反应的相互作用。两种酪氨酸激酶抑制剂金雀异黄素和酪氨酸蛋白B42呈剂量依赖性地增加cGMP的基础积聚浓度。蛋白激酶C的激活剂4-佛波酯(4-β-phorbol12-myriate，13-醋酸酯)可增强cGMP的积累，而蛋白激酶C的特异性抑制剂钙磷蛋白C(Calphostin C)则可阻断这种增加。酪氨酸激酶抑制剂对体外或PMA介导的PKC活性转位无影响。然而，当磷酸二酯酶被异丁基甲基黄嘌呤(IBMX)抑制时，酪氨酸激酶抑制剂单独或与PMA联合使用对cGMP的积累都没有影响，这表明磷酸二酯酶可能是这些抑制剂的作用部位。相比之下，Bayk 8644、离子霉素或KCl2诱导的细胞内钙离子浓度升高抑制了染料木素或酪蛋白B42介导的cGMP积聚的增加。这种抑制作用在IBMX存在时持续存在，并被钙/钙调蛋白抑制剂部分逆转。这些结果表明，PKC通过涉及酪氨酸磷酸化的信号通路来调节cGMP的降解速率。然而，钙离子提升剂对酪氨酸激酶抑制剂刺激的cGMP积累的抑制作用似乎不依赖于对磷酸二酯酶的抑制。
Inhibition of tyrosine kinase activities elevates cyclic GMP (cGMP) levels in rat pinealocytes. Since protein kinase C (PKC) and intracellular Ca2+both interact with the agonist-stimulated cGMP accumulation, in this study their interactions with the tyrosine kinase inhibitor-mediated cGMP response were investigated. Two tyrosine kinase inhibitors, genistein and tyrphostin B42, increased basal cGMP accumulation concentration dose-dependently. This increase in cGMP accumulation was potentiated by 4β-phorbol 12-myristate 13-acetate (PMA), an activator of PKC, and blocked by calphostin C, a specific PKC inhibitor. The tyrosine kinase inhibitors had no effect on the in vitro or PMA-mediated translocation of PKC activity. However, when the phosphodiesterase was inhibited by isobutylmethylxanthine (IBMX), neither the tyrosine kinase inhibitors alone nor in combination with PMA had an effect on cGMP accumulation, suggesting that phosphodiesterase is a probable site of action of the inhibitors. In comparison, elevation of intracellular Ca2+by BayK 8644, ionomycin, or KCl inhibited the genistein- or tyrphostin B42-mediated increase in cGMP accumulation. This inhibition persisted in the presence of IBMX and was partly reversed by a Ca2+/calmodulin inhibitor. These results suggest that PKC modulates the rate of cGMP degradation through signalling pathways involving tyrosine phosphorylation. However, the inhibitory effect of the Ca2+-elevating agents on the tyrosine kinase inhibitor stimulated cGMP accumulation appears to be independent of phosphodiesterase inhibition.