Targeting of diacylglycerol degradation to M1 muscarinic receptors by β-arrestins
Targeting of diacylglycerol degradation to M1 muscarinic receptors by β-arrestins
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DOI：
10.1126/science.1134562
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发表时间：
2007-02-02
期刊：
影响因子：
56.9
通讯作者：
Lefkowitz, Robert J.
中科院分区：
文献类型：
--
作者：
Nelson, Christopher D.;Perry, Stephen J.;Lefkowitz, Robert J.
七次跨膜受体 (7TMR) 信号传导由第二信使（如响应异三聚鸟嘌呤核苷酸结合蛋白 G(q) 产生的二酰基甘油 (DAG)）转导，并通过受体脱敏和第二信使的降解而终止。我们发现 β-抑制蛋白协调 G(q) 偶联 M1 毒蕈碱受体的两个过程。 β-抑制蛋白与二酰基甘油激酶 (DGK) 发生物理相互作用，二酰基甘油激酶是一种降解 DAG 的酶。此外，β-抑制蛋白对于激动剂刺激后 DAG 转化为磷脂酸至关重要，并且这种活性需要将 β-抑制蛋白-DGK 复合物募集到激活的 7TMR。 β-抑制蛋白的双重功能，即限制二酰基甘油的产生（通过受体脱敏），同时提高其降解速度，类似于它们将腺苷 3',5'-单磷酸磷酸二酯酶募集到 G(s) 偶联的 β(2)-肾上腺素能受体的能力。因此，β-抑制蛋白可以通过结构不同的酶降解化学上不同的第二信使，为不同类别的 7TMR 提供类似的调节功能。
Seven-transmembrane receptor (7TMR) signaling is transduced by second messengers such as diacylglycerol (DAG) generated in response to the heterotrimeric guanine nucleotide-binding protein G(q) and is terminated by receptor desensitization and degradation of the second messengers. We show that beta-arrestins coordinate both processes for the G(q)-coupled M1 muscarinic receptor. beta-Arrestins physically interact with diacylglycerol kinases (DGKs), enzymes that degrade DAG. Moreover, beta-arrestins are essential for conversion of DAG to phosphatidic acid after agonist stimulation, and this activity requires recruitment of the beta-arrestin-DGK complex to activated 7TMRs. The dual function of beta-arrestins, limiting production of diacylglycerol (by receptor desensitization) while enhancing its rate of degradation, is analogous to their ability to recruit adenosine 3',5'-monophosphate phosphodiesterases to G(s)-coupled beta(2)-adrenergic receptors. Thus, beta-arrestins can serve similar regulatory functions for disparate classes of 7TMRs through structurally dissimilar enzymes that degrade chemically distinct second messengers.