A novel non genomic glucocorticoid signaling mediated by a membrane palmitoylated glucocorticoid receptor cross talks with GnRH in gonadotrope cells
A novel non genomic glucocorticoid signaling mediated by a membrane palmitoylated glucocorticoid receptor cross talks with GnRH in gonadotrope cells
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DOI：
10.1038/s41598-017-01777-2
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发表时间：
2017-05-08
影响因子：
4.6
通讯作者：
Chauvin, Stephanie
中科院分区：
文献类型：
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作者：
Ayrout, Mohsen;Simon, Violaine;Chauvin, Stephanie
糖皮质激素（GC）是与生殖障碍相关的主要应激介质。GC通过激活主要作为转录因子的糖皮质激素受体（GR）发挥其作用。除了已建立的GR介导的基因组作用外，一些证据表明，在膜相关GR触发的促性腺激素细胞中，快速膜启动GC信号的作用。在这里，我们证明了在L β T2促性腺激素细胞中存在特定的膜启动GC信号，涉及两种相关磷酸化蛋白：Ca2+/钙调素依赖性蛋白激酶II （CaMKII）和突触素- 1。在5分钟内，应激范围为10(-7)M皮质酮或膜不透性gc， bsa偶联皮质酮处理的L β T2细胞显示出2倍的磷酸化camkii和磷酸化突触素- 1水平增加。生化方法显示，这种快速信号是由棕榈酰化的GR促进的。重要的是，GC显著改变了GnRH诱导的CaMKII磷酸化，这与GnRH受体和GC之间的新型串音一致。我们进一步观察了GC对小鼠垂体外植体LH释放的负面影响。总之，我们的工作提供了GC领域的新发现，通过对GR如何整合质膜的新理解，允许GC膜启动的信号在GnRH存在时不同，以破坏GnRH依赖的信号和LH分泌。
Glucocorticoid hormones (GC) are the main stress mediators associated with reproductive disorders. GC exert their effects through activation of the glucocorticoid receptor (GR) principally acting as a transcription factor. Beside well-established GR-mediated genomic actions, several lines of evidence suggest a role for rapid membrane-initiated GC signaling in gonadotrope cells triggered by a membrane-associated GR. Herein, we demonstrate the existence of a specific membrane-initiated GC signaling in L beta T2 gonadotrope cells involving two related phosphoproteins: Ca2+/Calmodulin-dependent protein kinase II (CaMKII) and synapsin-I. Within 5 min, L beta T2 cells treated with stress range of 10(-7) M Corticosterone or a membrane impermeable-GC, BSA-conjugated corticosterone, exhibited a 2-fold increase in levels of phospho-CaMKII and phospho-synapsin-I. Biochemical approaches revealed that this rapid signaling is promoted by a palmitoylated GR. Importantly, GC significantly alter GnRH-induced CaMKII phosphorylation, consistent with a novel cross-talk between the GnRH receptor and GC. This negative effect of GC on GnRH signaling was further observed on LH release by mouse pituitary explants. Altogether, our work provides new findings in GC field by bringing novel understanding on how GR integrates plasma membrane, allowing GC membrane-initiated signaling that differs in presence of GnRH to disrupt GnRH-dependent signaling and LH secretion.