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Physiological Reviews Apr 2003Regulated exocytosis of secretory granules or dense-core granules has been examined in many well-characterized cell types including neurons, neuroendocrine, endocrine,... (Review)
Review
Regulated exocytosis of secretory granules or dense-core granules has been examined in many well-characterized cell types including neurons, neuroendocrine, endocrine, exocrine, and hemopoietic cells and also in other less well-studied cell types. Secretory granule exocytosis occurs through mechanisms with many aspects in common with synaptic vesicle exocytosis and most likely uses the same basic protein components. Despite the widespread expression and conservation of a core exocytotic machinery, many variations occur in the control of secretory granule exocytosis that are related to the specialized physiological role of particular cell types. In this review we describe the wide range of cell types in which regulated secretory granule exocytosis occurs and assess the evidence for the expression of the conserved fusion machinery in these cells. The signals that trigger and regulate exocytosis are reviewed. Aspects of the control of exocytosis that are specific for secretory granules compared with synaptic vesicles or for particular cell types are described and compared to define the range of accessory control mechanisms that exert their effects on the core exocytotic machinery.
Topics: Animals; Exocytosis; Humans; Secretory Vesicles; Signal Transduction
PubMed: 12663867
DOI: 10.1152/physrev.00031.2002 -
Advances in Experimental Medicine and... 2019The secretory granules of pancreatic beta cells are specialized organelles responsible for the packaging, storage and secretion of the vital hormone insulin. The insulin... (Review)
Review
The secretory granules of pancreatic beta cells are specialized organelles responsible for the packaging, storage and secretion of the vital hormone insulin. The insulin secretory granules also contain more than 100 other proteins including the proteases involved in proinsulin-to insulin conversion, other precursor proteins, minor co-secreted peptides, membrane proteins involved in cell trafficking and ion translocation proteins essential for regulation of the intragranular environment. The synthesis, transport and packaging of these proteins into nascent granules must be carried out in a co-ordinated manner to ensure correct functioning of the granule. The process is regulated by many circulating nutrients such as glucose and can change under different physiological states. This chapter discusses the various processes involved in insulin granule biogenesis with a focus on the granule composition in health and disease.
Topics: Cytoplasmic Granules; Humans; Insulin; Insulin-Secreting Cells; Proinsulin; Secretory Vesicles
PubMed: 30919330
DOI: 10.1007/978-3-030-12668-1_2 -
Current Opinion in Cell Biology Dec 2023Regulated secretion, an essential cellular process, relies on secretory granules (SGs) for the controlled release of a diverse range of cargo molecules, including... (Review)
Review
Regulated secretion, an essential cellular process, relies on secretory granules (SGs) for the controlled release of a diverse range of cargo molecules, including proteins, peptides, hormones, enzymes, and neurotransmitters. SG biogenesis encompasses cargo selection, sorting, packaging, and trafficking, with the trans-Golgi Network (TGN) playing a central role. Research in the last three decades has revealed significant components required for SG biogenesis; however, no cargo receptor transferring granule cargo from the TGN to immature SGs (ISGs) has yet been identified. Consequently, recent research has devoted significant attention to studying receptor-independent cargo sorting mechanisms, shedding new light on the complexities of regulated secretion. Understanding the underlying molecular and biophysical mechanisms behind cargo sorting into ISGs holds great promise for advancing our knowledge of cellular communication and disease mechanisms.
Topics: trans-Golgi Network; Proteins; Protein Transport; Biological Transport; Secretory Vesicles
PubMed: 37657367
DOI: 10.1016/j.ceb.2023.102231 -
Critical Reviews in Biochemistry and... 2012Neurons and endocrine cells use a complex array of signaling molecules to communicate with each other and with various targets. The majority of these signaling molecules... (Review)
Review
Neurons and endocrine cells use a complex array of signaling molecules to communicate with each other and with various targets. The majority of these signaling molecules are stored in specialized organelles awaiting release on demand: 40-60 nm vesicles carry conventional or small molecule neurotransmitters, and 200-400 nm granules contain bioactive peptides. The supply of small molecule neurotransmitters is tightly regulated by local feedback of synthetic rates and transport processes at sites of release. The larger granules that contain bioactive peptides present the secretory cell with special challenges, as the peptide precursors are inserted into the lumen of the secretory pathway in the cell soma and undergo biosynthetic processing while being transported to distant sites for eventual secretion. One solution to this dilemma in information handling has been to employ proteolytic cleavage of secretory granule membrane proteins to produce cytosolic fragments that can signal to the nucleus, affecting gene expression. The use of regulated intramembrane proteolysis to signal from secretory granules to the nucleus is compared to its much better understood role in relaying information from the endoplasmic reticulum by SREBP and ATF6 and from the plasma membrane by cadherins, Notch and ErbB4.
Topics: Amyloid Precursor Protein Secretases; Animals; Cell Nucleus; Humans; Proteolysis; Secretory Vesicles; Signal Transduction
PubMed: 22681236
DOI: 10.3109/10409238.2012.694845 -
Trends in Cell Biology Mar 2001Regulated secretion of hormones occurs when a cell receives an external stimulus, triggering the secretory granules to undergo fusion with the plasma membrane and... (Review)
Review
Regulated secretion of hormones occurs when a cell receives an external stimulus, triggering the secretory granules to undergo fusion with the plasma membrane and release their content into the extracellular milieu. The formation of a mature secretory granule (MSG) involves a series of discrete and unique events such as protein sorting, formation of immature secretory granules (ISGs), prohormone processing and vesicle fusion. Regulated secretory proteins (RSPs), the proteins stored and secreted from MSGs, contain signals or domains to direct them into the regulated secretory pathway. Recent data on the role of specific domains in RSPs involved in sorting and aggregation suggest that the cell-type-specific composition of RSPs in the trans-Golgi network (TGN) has an important role in determining how the RSPs get into ISGs. The realization that lipid rafts are implicated in sorting RSPs in the TGN and the identification of SNARE molecules represent further major advances in our understanding of how MSGs are formed. At the heart of these findings is the elucidation of molecular mechanisms driving protein--lipid and protein--protein interactions specific for secretory granule biogenesis.
Topics: Cell Membrane; Chromogranins; Clathrin-Coated Vesicles; Furin; Membrane Fusion; Membrane Microdomains; Membrane Proteins; Organelle Biogenesis; Protein Binding; Protein Sorting Signals; Protein Transport; Proteins; SNARE Proteins; Secretory Vesicles; Subtilisins; Vesicular Transport Proteins; trans-Golgi Network
PubMed: 11306272
DOI: 10.1016/s0962-8924(00)01907-3 -
Trends in Endocrinology and Metabolism:... Jan 2003Secretory granules are found in specialized cell types, including endocrine cells, suggesting that a coordinated programme of gene expression is involved in their... (Review)
Review
Secretory granules are found in specialized cell types, including endocrine cells, suggesting that a coordinated programme of gene expression is involved in their biogenesis. Indeed, it has been proposed that chromogranin A (CgA) acts as an on/off switch for secretory granule biogenesis. However, this proposed function is difficult to reconcile with the large body of evidence suggesting that secretory granules exist in the absence of CgA and that cells can synthesize CgA in the absence of secretory granules. Indeed, recent evidence suggests that, rather than a master gene or universal on/off switch, a series of on/off switches combines to induce expression of subsets of secretory granule-associated genes. The assembly of newly synthesized proteins and the inclusion of existing granule proteins would produce functional secretory granules. CgA and related proteins might act as assembly factors in this process.
Topics: Animals; Chromogranin A; Chromogranins; Secretory Vesicles
PubMed: 12475606
DOI: 10.1016/s1043-2760(02)00011-5 -
Diabetes, Obesity & Metabolism Sep 2017Insulin secretory granule (SG) turnover consists of several highly regulated processes allowing for proper β-cell function and insulin secretion. Besides the spatial... (Review)
Review
Insulin secretory granule (SG) turnover consists of several highly regulated processes allowing for proper β-cell function and insulin secretion. Besides the spatial distribution of insulin SGs, their age has great impact on the likelihood of their secretion and their behaviour within the β-cell. While quantitative measurements performed decades ago demonstrated the preferential secretion of young insulin, new experimental approaches aim to investigate insulin ageing at the granular level. Live-cell imaging, automated image analysis and correlative light and electron microscopy have fostered knowledge of age-defined insulin SG dynamics, their interaction with the cytoskeleton and ultrastructural features. Here, we review our recent work in regards to the connection between insulin SG age, SG dynamics, intracellular location and interaction with other proteins.
Topics: Animals; Exocytosis; Humans; Image Processing, Computer-Assisted; Imaging, Three-Dimensional; Insulin; Insulin Secretion; Insulin-Secreting Cells; Microscopy, Electron, Transmission; Microscopy, Fluorescence; Models, Biological; Organelle Biogenesis; Secretory Pathway; Secretory Vesicles
PubMed: 28880479
DOI: 10.1111/dom.13015 -
Physiology (Bethesda, Md.) Apr 2006The dense-core secretory granule is a key organelle for secretion of hormones and neuropeptides in endocrine cells and neurons, in response to stimulation. Cholesterol... (Review)
Review
The dense-core secretory granule is a key organelle for secretion of hormones and neuropeptides in endocrine cells and neurons, in response to stimulation. Cholesterol and granins are critical for the assembly of these organelles at the trans-Golgi network, and their biogenesis is regulated quantitatively by posttranscriptional and posttranslational mechanisms.
Topics: Animals; Cholesterol; Chromogranins; Endocrine System; Golgi Apparatus; Hormones; Humans; Lipids; Neurons; Neuropeptides; Protein Processing, Post-Translational; Secretory Vesicles
PubMed: 16565478
DOI: 10.1152/physiol.00043.2005 -
Journal of Neurochemistry Jun 2016The regulated secretory pathway begins with the formation of secretory granules by budding from the Golgi apparatus and ends by their fusion with the plasma membrane... (Review)
Review
The regulated secretory pathway begins with the formation of secretory granules by budding from the Golgi apparatus and ends by their fusion with the plasma membrane leading to the release of their content into the extracellular space, generally following a rise in cytosolic calcium. Generation of these membrane-bound transport carriers can be classified into three steps: (i) cargo sorting that segregates the cargo from resident proteins of the Golgi apparatus, (ii) membrane budding that encloses the cargo and depends on the creation of appropriate membrane curvature, and (iii) membrane fission events allowing the nascent carrier to separate from the donor membrane. These secretory vesicles then mature as they are actively transported along microtubules toward the cortical actin network at the cell periphery. The final stage known as regulated exocytosis involves the docking and the priming of the mature granules, necessary for merging of vesicular and plasma membranes, and the subsequent partial or total release of the secretory vesicle content. Here, we review the latest evidence detailing the functional roles played by lipids during secretory granule biogenesis, recruitment, and exocytosis steps. In this review, we highlight evidence supporting the notion that lipids play important functions in secretory vesicle biogenesis, maturation, recruitment, and membrane fusion steps. These effects include regulating various protein distribution and activity, but also directly modulating membrane topology. The challenges ahead to understand the pleiotropic functions of lipids in a secretory granule's journey are also discussed. This article is part of a mini review series on Chromaffin cells (ISCCB Meeting, 2015).
Topics: Animals; Biological Transport; Calcium; Cytoplasmic Granules; Exocytosis; Humans; Lipids; Membrane Fusion; Secretory Vesicles
PubMed: 26877188
DOI: 10.1111/jnc.13577 -
Proceedings of the National Academy of... Oct 2022Mucins are large, highly glycosylated transmembrane and secreted proteins that line and protect epithelial surfaces. However, the details of mucin biosynthesis and...
Mucins are large, highly glycosylated transmembrane and secreted proteins that line and protect epithelial surfaces. However, the details of mucin biosynthesis and packaging in vivo are largely unknown. Here, we demonstrate that multiple distinct mucins undergo intragranular restructuring during secretory granule maturation in vivo, forming unique structures that are spatially segregated within the same granule. We further identify temporally-regulated genes that influence mucin restructuring, including those controlling pH (), Ca ions () and Cl ions ( and ). Finally, we show that altered mucin glycosylation influences the dimensions of these structures, thereby affecting secretory granule morphology. This study elucidates key steps and factors involved in intragranular, rather than intergranular segregation of mucins through regulated restructuring events during secretory granule maturation. Understanding how multiple distinct mucins are efficiently packaged into and secreted from secretory granules may provide insight into diseases resulting from defects in mucin secretion.
Topics: Cytoplasmic Granules; Glycosylation; Mucins; Secretory Vesicles
PubMed: 36252017
DOI: 10.1073/pnas.2209750119