Regulated RalBP1 Binding to RalA and PSD-95 Controls AMPA Receptor Endocytosis and LTD
Kihoon HanMyoung‐Hwan KimDaniel P. SeeburgJinsoo SeoChiara VerpelliSeungnam HanHye Sun ChungJaewon KoHyun Woo LeeKaram KimWon Do HeoTobias MeyerHyun KimCarlo SalaSe‐Young ChoiMorgan ShengEunjoon Kim
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Abstract:
Long-term depression (LTD) is a long-lasting activity-dependent decrease in synaptic strength. NMDA receptor (NMDAR)–dependent LTD, an extensively studied form of LTD, involves the endocytosis of AMPA receptors (AMPARs) via protein dephosphorylation, but the underlying mechanism has remained unclear. We show here that a regulated interaction of the endocytic adaptor RalBP1 with two synaptic proteins, the small GTPase RalA and the postsynaptic scaffolding protein PSD-95, controls NMDAR-dependent AMPAR endocytosis during LTD. NMDAR activation stimulates RalA, which binds and translocates widespread RalBP1 to synapses. In addition, NMDAR activation dephosphorylates RalBP1, promoting the interaction of RalBP1 with PSD-95. These two regulated interactions are required for NMDAR-dependent AMPAR endocytosis and LTD and are sufficient to induce AMPAR endocytosis in the absence of NMDAR activation. RalA in the basal state, however, maintains surface AMPARs. We propose that NMDAR activation brings RalBP1 close to PSD-95 to promote the interaction of RalBP1-associated endocytic proteins with PSD-95-associated AMPARs. This suggests that scaffolding proteins at specialized cellular junctions can switch their function from maintenance to endocytosis of interacting membrane proteins in a regulated manner.This chapter contains sections titled: Introduction Vesicle Formation in the Endocytic Pathway Clathrin-Coated Vesicles Ubiquitinylation as a Receptor Degradation Signal Caveolae in the Hepatocyte Lipids and Phosphoinositides as Regulators of Endocytosis Rab Proteins in Endocytic Traffic Hepatocyte-Specific Endocytic Membrane Traffic Hepatitis Viruses: Masters of Hepatocellular Endocytosis Future Directions References
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Abstract Endocytosis involves plasma membrane-derived vesicles for the recycling of intra- and extracellular components. Increasing evidence suggests that endocytosis is related to maintaining intracellular homeostasis and defense against disease. Consequently, investigation of the endocytic pathway attracts considerable scientific interest. This study reports live-cell imaging of endocytosis using the newly-developed fluorescent probe ECGreen. We demonstrate that ECGreen is not membrane permeable and its fluorescence signal increases in acidic conditions. Because of these characteristics, ECGreen remains on the plasma membrane, and then shows increased fluorescence when it is internalized into the acidic vesicles formed in the endocytic process. ECGreen allows direct observation of the internalized vesicle; it is a valuable new probe for endocytic imaging.
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ABSTRACT Endocytosis mediates the cellular uptake of numerous molecules from the extracellular space and is a fundamentally important process. In the renal proximal tubule, the scavenger receptor megalin and its co-receptor cubilin mediate endocytosis of low molecular weight proteins from the renal filtrate. However, the extent to which megalin endocytosis relies on different components of the trafficking machinery remains relatively poorly defined in vivo. In this study, we identify a functional requirement for the F-BAR protein pacsin2 in endocytosis in the renal proximal tubule of zebrafish larvae. Pacsin2 is expressed throughout development and in all zebrafish tissues, similar to the mammalian orthologue. Within renal tubular epithelial cells, pacsin2 is enriched at the apical pole where it is localised to endocytic structures. Loss of pacsin2 results in reduced endocytosis within the proximal tubule, which is accompanied by a reduction in the abundance of megalin and endocytic organelles. Our results indicate that pacsin2 is required for efficient endocytosis in the proximal tubule, where it likely cooperates with other trafficking machinery to maintain endocytic uptake and recycling of megalin.
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Endocytosis is the process by which molecules are actively transported into cells. It can take on a variety of forms depending on the cellular machinery involved ranging from specific receptor-mediated endocytosis to the less selective and actin-driven macropinocytosis. The plasma lipoproteins, which deliver lipids and other cargo to cells, have been intensely studied with respect to their endocytic uptake. One of the first molecules to be visualised undergoing endocytosis via a receptor-mediated, clathrin-dependent pathway was low-density lipoprotein (LDL). The LDL molecule has subsequently been shown to be internalised through multiple endocytic pathways. Dissecting the pathways of lipoprotein endocytosis has been crucial to understanding the regulation of plasma lipid levels and how lipids enter cells in the arterial wall to promote atherosclerosis. It has also aided understanding of the dysregulation that occurs in plasma lipid levels when molecules involved in uptake are defective, as is the case in familial hypercholesterolemia (FH). The aim of this review is to outline the many endocytic pathways utilised for lipoprotein uptake. It explores the various experimental approaches that have been applied to visualise lipoprotein endocytosis with an emphasis on LDL and its more complex counterpart, lipoprotein(a) [Lp(a)]. Finally, we look at new developments in lipoprotein visualisation that hold promise for scrutinising endocytic pathways to finer detail in the future.
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尽管花粉试管生长是为更高的植物授精和种子生产的一个前提，导致花粉试管排放和延伸的过程为理解尖端生长的基本机制是关键的。在他们与顶端的血浆膜(下午) 的一个限制区域被认为到保险丝的地方，花粉试管延伸在顶端的区域，或清楚的地区由导出 Golgi 的能分泌的泡(SV ) 的累积和熔化发生，这通常被接受，定义顶端的生长领域。在尖端的 SV 的熔化在房间墙材料外面逆行并且提供下午的新片断。然而，电子显微镜学研究清楚地证明了极大地在尖端合并的 PM 超过延伸，下午检索的机制已经被要求在中间 -- 第十九个世纪。endocytosis 上的最近的研究在花粉试管生长期间证明不同 endocytic 小径发生在试管的不同地区，包括顶，并且导致了一个新假设在尖端解释泡累积；也就是， endocytic 泡除了 SV 和那 exocytosis 实质地作出贡献到塑造 V 的泡累积，这不包含全部顶端的领域。新卓见建议了在在顶的 exo- 和 endocytosis 之间的调整贡献的吸引人的假设以类脂化合物 / 蛋白质作文和能在房间的生理学有不同功能的显示出的不同降级小径维持下午极性。在 vivo 的花粉试管生长被和风格分子的相互作用仔细调整。在花粉试管再循环的 endocytosis 和膜的学习打开新观点到在 vivo 学习花粉试管风格相互作用。
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