Insulin disrupts beta-adrenergic signalling to protein kinase A in adipocytes.
Insulin disrupts beta-adrenergic signalling to protein kinase A in adipocytes.
复制标题
DOI：
--
复制
发表时间：
2005
期刊：
影响因子：
64.8
通讯作者：
Jin Zhang;C. Hupfeld;Susan S. Taylor;J. Olefsky;R. Tsien
中科院分区：
文献类型：
--
作者：
Jin Zhang;C. Hupfeld;Susan S. Taylor;J. Olefsky;R. Tsien
激素动员细胞内的第二信使，并启动涉及蛋白激酶和磷酸酶的信号级联，这两种信号通常通过锚定蛋白质来增加信号特异性。这些支架蛋白本身可能受到荷尔蒙的调节。在脂肪细胞中，β-肾上腺素能受体的刺激增加了环磷酸腺苷的水平，并激活了蛋白激酶A(PKA)，蛋白激酶A通过磷酸化激素敏感的脂肪酶和Perilipin来刺激脂肪分解。急性胰岛素治疗可激活磷酸二酯酶3B，降低cAMP水平，并抑制β-肾上腺素能受体信号。相反，慢性高胰岛素血症(典型的2型糖尿病)会增加β-肾上腺素能受体介导的cAMP的产生。这种cAMP信号的放大是矛盾的，因为它应该加强脂肪分解，而这与已知的高胰岛素血症的短期影响相反。在这里，我们表明，在脂肪细胞中，长期高水平的胰岛素抑制了β-肾上腺素能受体(但不是其他cAMP升高刺激)激活PKA。我们使用改进的荧光报告和内源性cAMP反应元件结合蛋白(CREB)的磷酸化来测量这一点。PKA支架的破坏模拟了胰岛素对β-肾上腺素能受体信号的干扰。长期高胰岛素水平可能扰乱β-肾上腺素能受体与PKA的紧密结合，为异源信号转导通路之间的串扰确定了一种新的机制。
Hormones mobilize intracellular second messengers and initiate signalling cascades involving protein kinases and phosphatases, which are often spatially compartmentalized by anchoring proteins to increase signalling specificity. These scaffold proteins may themselves be modulated by hormones. In adipocytes, stimulation of beta-adrenergic receptors increases cyclic AMP levels and activates protein kinase A (PKA), which stimulates lipolysis by phosphorylating hormone-sensitive lipase and perilipin. Acute insulin treatment activates phosphodiesterase 3B, reduces cAMP levels and quenches beta-adrenergic receptor signalling. In contrast, chronic hyperinsulinaemic conditions (typical of type 2 diabetes) enhance beta-adrenergic receptor-mediated cAMP production. This amplification of cAMP signalling is paradoxical because it should enhance lipolysis, the opposite of the known short-term effect of hyperinsulinaemia. Here we show that in adipocytes, chronically high insulin levels inhibit beta-adrenergic receptors (but not other cAMP-elevating stimuli) from activating PKA. We measured this using an improved fluorescent reporter and by phosphorylation of endogenous cAMP-response-element binding protein (CREB). Disruption of PKA scaffolding mimics the interference of insulin with beta-adrenergic receptor signalling. Chronically high insulin levels may disrupt the close apposition of beta-adrenergic receptors and PKA, identifying a new mechanism for crosstalk between heterologous signal transduction pathways.