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胆固醇通过增强突触融合蛋白 1 诱导的膜弯曲对钙依赖性囊泡融合的需求。

Requirement of Cholesterol for Calcium-Dependent Vesicle Fusion by Strengthening Synaptotagmin-1-Induced Membrane Bending.

机构信息

Neurological Disorders Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha, Qatar.

HBKU Core Labs, Hamad Bin Khalifa University (HBKU), Doha, Qatar.

出版信息

Adv Sci (Weinh). 2023 May;10(15):e2206823. doi: 10.1002/advs.202206823. Epub 2023 Apr 14.

DOI:10.1002/advs.202206823
PMID:37058136
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10214243/
Abstract

Cholesterol is essential for neuronal activity and function. Cholesterol depletion in the plasma membrane impairs synaptic transmission. However, the molecular mechanisms by which cholesterol deficiency leads to defects in vesicle fusion remain poorly understood. Here, it is shown that cholesterol is required for Ca -dependent native vesicle fusion using the in vitro reconstitution of fusion and amperometry to monitor exocytosis in chromaffin cells. Purified native vesicles are crucial for the reconstitution of physiological Ca -dependent fusion, because vesicle-mimicking liposomes fail to reproduce the cholesterol effect. Intriguingly, cholesterol has no effect on the membrane binding of synaptotagmin-1, a Ca sensor for ultrafast fusion. Cholesterol strengthens local membrane deformation and bending induced by synaptotagmin-1, thereby lowering the energy barrier for Ca -dependent fusion to occur. The data provide evidence that cholesterol depletion abolishes Ca -dependent vesicle fusion by disrupting synaptotagmin-1-induced membrane bending, and suggests that cholesterol is an essential lipid regulator for Ca -dependent fusion.

摘要

胆固醇对于神经元的活动和功能至关重要。质膜中的胆固醇耗竭会损害突触传递。然而，胆固醇缺乏导致囊泡融合缺陷的分子机制仍知之甚少。本文使用体外融合重构和安培法监测嗜铬细胞中胞吐作用的方法，显示了胆固醇在 Ca 依赖性原生囊泡融合中的必要性。纯化的原生囊泡对于生理 Ca 依赖性融合的重构至关重要，因为囊泡模拟脂质体无法再现胆固醇的作用。有趣的是，胆固醇对突触融合蛋白相关蛋白 1（一种超快融合的 Ca 传感器）的膜结合没有影响。胆固醇增强了突触融合蛋白相关蛋白 1诱导的局部膜变形和弯曲，从而降低了 Ca 依赖性融合发生的能量障碍。这些数据提供了证据表明，胆固醇耗竭通过破坏突触融合蛋白相关蛋白 1诱导的膜弯曲而废除 Ca 依赖性囊泡融合，并表明胆固醇是 Ca 依赖性融合的必需脂质调节剂。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c93/10214243/3ae79344ab8f/ADVS-10-2206823-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c93/10214243/26744a560711/ADVS-10-2206823-g007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c93/10214243/ece436079075/ADVS-10-2206823-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c93/10214243/fe7af9a6fab0/ADVS-10-2206823-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c93/10214243/3ae79344ab8f/ADVS-10-2206823-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c93/10214243/26744a560711/ADVS-10-2206823-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c93/10214243/6265773830fc/ADVS-10-2206823-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c93/10214243/119cbf0837b3/ADVS-10-2206823-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c93/10214243/e14e2b42c9a7/ADVS-10-2206823-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c93/10214243/ece436079075/ADVS-10-2206823-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c93/10214243/fe7af9a6fab0/ADVS-10-2206823-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c93/10214243/3ae79344ab8f/ADVS-10-2206823-g004.jpg

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