Luteinizing Hormone Causes Phosphorylation and Activation of the cGMP Phosphodiesterase PDE5 in Rat Ovarian Follicles, Contributing, Together with PDE1 Activity, to the Resumption of Meiosis.
Luteinizing Hormone Causes Phosphorylation and Activation of the cGMP Phosphodiesterase PDE5 in Rat Ovarian Follicles, Contributing, Together with PDE1 Activity, to the Resumption of Meiosis.
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DOI：
10.1095/biolreprod.115.135897
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发表时间：
2016-05
影响因子：
3.6
通讯作者：
Jaffe LA
中科院分区：
文献类型：
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作者：
Egbert JR;Uliasz TF;Shuhaibar LC;Geerts A;Wunder F;Kleiman RJ;Humphrey JM;Lampe PD;Artemyev NO;Rybalkin SD;Beavo JA;Movsesian MA;Jaffe LA
排卵前卵泡中哺乳动物卵母细胞的减数分裂细胞周期通过 cGMP 从周围颗粒细胞扩散到卵母细胞中而处于前期停滞状态。然后，黄体生成素 (LH) 通过降低颗粒细胞中的 cGMP 来释放减数分裂停滞。 LH 诱导的 cGMP 减少部分是由鸟苷酸环化酶活性降低引起的，但观察到 cGMP 磷酸二酯酶 PDE5 在 LH 信号传导过程中被磷酸化，表明 PDE5 活性的增加也可能有所贡献。为了研究这个想法，我们测量了大鼠卵泡中的 cGMP 水解活性。基础活性主要归因于 PDE1A 和 PDE5，LH 增加 PDE5 活性。 PDE5 活性的增加伴随着 PDE5 在丝氨酸 92（蛋白激酶 A/G 共有位点）处的磷酸化。升高cAMP可促进磷酸化和活性增加，而抑制蛋白激酶A则可抑制磷酸化和活性的增加，这支持了LH通过蛋白激酶A刺激PDE5磷酸化来激活PDE5的假设。核膜破裂表明，抑制PDE5活性部分抑制了LH诱导的减数分裂恢复，但需要同时抑制PDE5和PDE1活性才能完全抑制这种反应。这些结果表明，PDE5 和 PDE1 的活性都有助于 LH 诱导的大鼠卵母细胞减数分裂的恢复，并且 PDE5 的磷酸化和激活是一种调节机制。
The meiotic cell cycle of mammalian oocytes in preovulatory follicles is held in prophase arrest by diffusion of cGMP from the surrounding granulosa cells into the oocyte. Luteinizing hormone (LH) then releases meiotic arrest by lowering cGMP in the granulosa cells. The LH-induced reduction of cGMP is caused in part by a decrease in guanylyl cyclase activity, but the observation that the cGMP phosphodiesterase PDE5 is phosphorylated during LH signaling suggests that an increase in PDE5 activity could also contribute. To investigate this idea, we measured cGMP-hydrolytic activity in rat ovarian follicles. Basal activity was due primarily to PDE1A and PDE5, and LH increased PDE5 activity. The increase in PDE5 activity was accompanied by phosphorylation of PDE5 at serine 92, a protein kinase A/G consensus site. Both the phosphorylation and the increase in activity were promoted by elevating cAMP and opposed by inhibiting protein kinase A, supporting the hypothesis that LH activates PDE5 by stimulating its phosphorylation by protein kinase A. Inhibition of PDE5 activity partially suppressed LH-induced meiotic resumption as indicated by nuclear envelope breakdown, but inhibition of both PDE5 and PDE1 activities was needed to completely inhibit this response. These results show that activities of both PDE5 and PDE1 contribute to the LH-induced resumption of meiosis in rat oocytes, and that phosphorylation and activation of PDE5 is a regulatory mechanism.