Department of Reproductive Medicine, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0674, USA.
Mol Cell Endocrinol. 2009 Nov 13;311(1-2):47-54. doi: 10.1016/j.mce.2009.07.014. Epub 2009 Jul 24.
The integrated signaling of insulin and gonadotropin-releasing hormone in the pituitary gonadotropes may have a profound bearing on reproductive function, although the cross-receptor signaling mechanisms are unclear. We demonstrate that the insulin receptor is constitutively localized to non-caveolar lipid raft microdomains in the pituitary gonadotrope cell line LbetaT2. The localization to rafts is consistent with similar localization of the GnRH receptor. Insulin receptor phosphorylation occurs in raft domains and activates the downstream signaling targets Insulin Receptor Substrate1 and Akt/Protein Kinase B. Although insulin alone does not strongly activate the extracellular signal-regulated kinase second messenger cascade, co-stimulation potentiates the phosphorylation of the extracellular signal-regulated kinase by gonadotropin-releasing hormone. The co-stimulatory effect of insulin and gonadotropin-releasing hormone is also evident in increased activation of cap-dependent translation. In contrast, co-stimulation attenuates Akt/Protein Kinase B activation. Our results show that both gonadotropin-releasing hormone and insulin are capable of mutually altering their respective regulatory signaling cascades. We suggest that this provides a mechanism to integrate neuropeptide and energy homeostatic signals to modulate reproductive function.
胰岛素和促性腺激素释放激素在垂体促性腺激素中的整合信号可能对生殖功能有深远的影响，尽管交叉受体信号机制尚不清楚。我们证明，胰岛素受体在垂体促性腺激素细胞系 LbetaT2 中持续定位于非 caveolar 脂筏微域。这种定位与 GnRH 受体的类似定位一致。胰岛素受体磷酸化发生在筏域，并激活下游信号靶标胰岛素受体底物 1 和 Akt/蛋白激酶 B。尽管胰岛素本身不能强烈激活细胞外信号调节激酶第二信使级联，但共刺激增强了促性腺激素释放激素对细胞外信号调节激酶的磷酸化。胰岛素和促性腺激素释放激素的共刺激作用也表现在增加了帽依赖性翻译的激活。相比之下，共刺激会减弱 Akt/蛋白激酶 B 的激活。我们的研究结果表明，促性腺激素释放激素和胰岛素都能够相互改变各自的调节信号级联。我们认为，这提供了一种整合神经肽和能量稳态信号的机制，以调节生殖功能。
