Phosphatidylinositol 4,5-bisphosphate is regenerated by speeding of the PI 4-kinase pathway during long PLC activation.
Phosphatidylinositol 4,5-bisphosphate is regenerated by speeding of the PI 4-kinase pathway during long PLC activation.
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DOI：
10.1085/jgp.202012627
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发表时间：
2020-12-07
期刊：
影响因子：
--
通讯作者：
Hille B
中科院分区：
文献类型：
--
作者：
Myeong J;de la Cruz L;Jung SR;Yeon JH;Suh BC;Koh DS;Hille B
毒蕈碱Gq偶联受体的刺激最初从质膜消耗磷酸肌醇磷脂酰肌醇4，5-二磷酸。Myeong等人表明，由于PI 4-激酶途径的显著加速而不是受体的脱敏，磷酸肌醇随后在持续的受体刺激期间再生。膜磷脂酰肌醇脂质的动态代谢涉及几个细胞区室，包括ER、高尔基体和质膜。存在磷酸化和去磷酸化以及合成、转移和分解的循环。简化的磷酸肌醇循环包括ER中磷脂酰肌醇的合成、高尔基体和质膜中的转运和磷酸化以产生磷脂酰肌醇4，5-二磷酸，随后是质膜中受体刺激的水解和组分返回ER用于重组。使用特定的脂质种类的探针，我们已经遵循和分析了这些事件的动力学过程中的几个M1毒蕈碱受体的刺激耦合到G-蛋白Gq。我们表明，在长期持续的激动剂作用，多磷酸化肌醇脂质最初耗尽，但然后再生，而激动剂仍然存在。实验和动力学模型表明，再生的结果逐渐但大量的PI 4-激酶途径的上调，而不是从脱敏的受体。磷脂酰肌醇4-磷酸和脂质激酶PI 4KIII α（PI 4KA）的高尔基体池有助于这种稳态再生。这种强大的加速，这可能是在酶活性或前体和产品交付的水平，揭示了在磷酸肌醇循环的强有力的监管控制。
Stimulation of muscarinic Gq-coupled receptors initially depletes phosphoinositide phosphatidylinositol 4,5-bisphosphate from the plasma membrane. Myeong et al. show that phosphoinositides subsequently regenerate during sustained receptor stimulation as a consequence of profound PI 4-kinase pathway acceleration and not desensitization of receptors. The dynamic metabolism of membrane phosphoinositide lipids involves several cellular compartments including the ER, Golgi, and plasma membrane. There are cycles of phosphorylation and dephosphorylation and of synthesis, transfer, and breakdown. The simplified phosphoinositide cycle comprises synthesis of phosphatidylinositol in the ER, transport, and phosphorylation in the Golgi and plasma membranes to generate phosphatidylinositol 4,5-bisphosphate, followed by receptor-stimulated hydrolysis in the plasma membrane and return of the components to the ER for reassembly. Using probes for specific lipid species, we have followed and analyzed the kinetics of several of these events during stimulation of M1 muscarinic receptors coupled to the G-protein Gq. We show that during long continued agonist action, polyphosphorylated inositol lipids are initially depleted but then regenerate while agonist is still present. Experiments and kinetic modeling reveal that the regeneration results from gradual but massive up-regulation of PI 4-kinase pathways rather than from desensitization of receptors. Golgi pools of phosphatidylinositol 4-phosphate and the lipid kinase PI4KIIIα (PI4KA) contribute to this homeostatic regeneration. This powerful acceleration, which may be at the level of enzyme activity or of precursor and product delivery, reveals strong regulatory controls in the phosphoinositide cycle.
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影响因子：
7.7
作者：
Chung J;Nakatsu F;Baskin JM;De Camilli P
通讯作者：
De Camilli P
影响因子：
--
作者：
Cowan, Ann E.;Moraru, Ion I.;Schaff, James C.;Slepchenko, Boris M.;Loew, Leslie M.
通讯作者：
Loew, Leslie M.
DOI：
10.1085/jgp.201210886
发表时间：
2013-05
期刊：
The Journal of general physiology
影响因子：
--
作者：
Dickson EJ;Falkenburger BH;Hille B
通讯作者：
Hille B
影响因子：
4.8
作者：
de Barry, Jean;Janoshazi, Agnes;Vitale, Nicolas
通讯作者：
Vitale, Nicolas
影响因子：
4.8
作者：
Chang, Chi-Lun;Liou, Jen
通讯作者：
Liou, Jen