Insulin disrupts β-adrenergic signalling to protein kinase A in adipocytes

被引:240
作者
Zhang, J
Hupfeld, CJ
Taylor, SS
Olefsky, JM
Tsien, RY [1 ]
机构
[1] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA
[2] Univ Calif San Diego, Div Endocrinol & Metab, La Jolla, CA 92093 USA
[3] Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92093 USA
[4] Univ Calif San Diego, Howard Hughes Med Inst, La Jolla, CA 92093 USA
基金
美国国家卫生研究院;
关键词
D O I
10.1038/nature04140
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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(1). These scaffold proteins may themselves be modulated by hormones(2 - 4). In adipocytes, stimulation of beta- adrenergic receptors increases cyclic AMP levels and activates protein kinase A ( PKA)(5), which stimulates lipolysis by phosphorylating hormone- sensitive lipase and perilipin(6 - 8). Acute insulin treatment activates phosphodiesterase 3B, reduces cAMP levels and quenches beta- adrenergic receptor signalling(9). In contrast, chronic hyperinsulinaemic conditions ( typical of type 2 diabetes) enhance beta- adrenergic receptor- mediated cAMP production(10). 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.
引用
收藏
页码:569 / 573
页数:5
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