Dense‐core vesicle biogenesis and exocytosis in neurons lacking chromogranins A and B

Domínguez, Natalia; Weering, Jan R.T. van; Borges, Ricardo; Toonen, Ruud F.; Verhage, Matthijs

doi:10.1111/jnc.14263

Cited by 27 publications

(25 citation statements)

References 46 publications

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“…In this report, we show that loss of CgB in the pancreatic islet β-cell has significant effects on glucose-stimulated insulin secretion directly related to its role in granule protein trafficking. Previous studies have demonstrated that loss of CgB negatively impacts hormone release in some endocrine tissues, such as pancreatic islets (Obermüller et al, 2010) and adrenal chromaffin cells (Díaz-Vera et al, 2012;Dominguez et al, 2018), but is dispensable in other cell types including hippocampal neurons (Dominguez et al, 2018). Fig.…”

Section: Discussionmentioning

confidence: 91%

“…Additionally, granins may chaperone the sorting and/or deposition of secretory cargo, such as prohormones, within the budding granule (Natori and Huttner, 1996), though direct associations with prohormones have yet to be documented. Reduced expression of some granins, such as CgB, has been reported in human T2D islets (Bugliani et al, 2013); however, conflicting knockout studies have hampered clear delineation of its role(s) in granule biology (Díaz-Vera et al, 2012;Hendy et al, 2006;Mahapatra et al, 2005;Dominguez et al, 2018). Global deletion of CgB reduces islet hormone secretion (glucagon, insulin and somatostatin) (Obermüller et al, 2010); however, ultrastructrural analysis failed to reveal defects in granule structure and number, suggesting CgB is not required for dense core granule formation.…”

Section: Introductionmentioning

confidence: 99%

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Chromogranin B regulates early-stage insulin granule trafficking from the Golgi in pancreatic islet β-cells

Bearrows

Bauchle

Becker

et al. 2019

Journal of Cell Science

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Chromogranin B (CgB, also known as CHGB) is abundantly expressed in dense core secretory granules of multiple endocrine tissues and has been suggested to regulate granule biogenesis in some cell types, including the pancreatic islet β-cell, though the mechanisms are poorly understood. Here, we demonstrate a critical role for CgB in regulating secretory granule trafficking in the β-cell. Loss of CgB impairs glucosestimulated insulin secretion, impedes proinsulin processing to yield increased proinsulin content, and alters the density of insulin-containing granules. Using an in situ fluorescent pulse-chase strategy to track nascent proinsulin, we show that loss of CgB impairs Golgi budding of proinsulin-containing secretory granules, resulting in a substantial delay in trafficking of nascent granules to the plasma membrane with an overall decrease in total plasma membrane-associated granules. These studies demonstrate that CgB is necessary for efficient trafficking of secretory proteins into the budding granule, which impacts the availability of insulin-containing secretory granules for exocytic release. This article has an associated First Person interview with the first author of the paper.

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Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Chromogranin B regulates early-stage insulin granule trafficking from the Golgi in pancreatic islet β-cells

Bearrows

Bauchle

Becker

et al. 2019

Journal of Cell Science

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“…To investigate the precise role of CgA among all granins expressed in a same secretory cell, the Borges's group generated a double CgA/CgB‐KO mouse line, and observed that the absence of both granins led to giant SG‐like structures with little or no electron dense internal matrix, changes in catecholamine accumulation and in the exocytosis course with a significant reduction of the secretory response in chromaffin cells, indicating an alteration of vesicular catecholamine storage and secretion capacities . Recently, SG biogenesis was investigated in hippocampal neurons from CgA/CgB‐KO mice and surprisingly, no changes were detected in CgA/CgB‐KO neurons which exhibited normal dendritic and axonal length and arborization, synapse density, and synaptic vesicle accumulation, as well as number of secretogranin II (SgII)‐positive SGs and exocytotic events . Thus, the granulogenic activity of CgA, as well as its role in neurosecretion maintenance, appear to be cell‐dependent and despite the biochemical properties shared between CgA and CgB, CgB is unable to restore SG biogenesis in CgA‐deficient PC12 cells (6T3 cells) …”

Section: Chromogranin a Contributes To The Biogenesis Of Secretory Grmentioning

confidence: 99%

“…22,23 Recently, SG biogenesis was investigated in hippocampal neurons from CgA/CgB-KO mice and surprisingly, no changes were detected in CgA/CgB-KO neurons which exhibited normal dendritic and axonal length and arborization, synapse density, and synaptic vesicle accumulation, as well as number of secretogranin II (SgII)-positive SGs and exocytotic events. 24 Thus, the granulogenic activity of CgA, as well as its role in neurosecretion maintenance, appear to be cell-dependent and despite the biochemical properties shared between CgA and CgB, CgB is unable to restore SG biogenesis in CgA-deficient PC12 cells (6T3 cells). 25…”

Section: Chromogranin a Contributes To The Biogenesis Of Secretory mentioning

confidence: 99%

Chromogranin A in the early steps of the neurosecretory pathway

2019

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Chromogranin A (CgA) is a soluble glycoprotein stored with hormones and neuropeptides in secretory granules (SG) of most (neuro)endocrine cells and neurons. Since its discovery in 1967, many studies have reported its structural characteristics, biological roles, and mechanisms of action. Indeed, CgA is both a precursor of various biologically active peptides and a granulogenic protein regulating the storage and secretion of hormones and neuropeptides. This review emphasizes the findings and theoretical concepts around the CgA‐linked molecular machinery controlling hormone/neuropeptide aggregation and the interaction of CgA‐hormone/neuropeptide aggregates with the trans‐Golgi membrane to allow hormone/neuropeptide targeting and SG biogenesis. We will also discuss the intriguing alteration of CgA expression and secretion in various neurological disorders, which could provide insights to elucidate the molecular mechanisms underlying these pathophysiological conditions.

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“…Independently from their cargo, LDCVs express a series of integral proteins that, biochemically, make them a relatively homogeneous population of vesicles. Among these are the chromogranins (Bartolomucci et al, 2011 ), which are important regulators of cargo sorting in LDCVs biogenesis, although very recent work in mouse hippocampal neurons has demonstrated that they are not indispensable for LDCVs’ exocytosis (Dominguez et al, 2018 ).…”

Section: State Of Art On High Molecular Weight Neurotransmitter Localmentioning

confidence: 99%

Costorage of High Molecular Weight Neurotransmitters in Large Dense Core Vesicles of Mammalian Neurons

Merighi

2018

Front. Cell. Neurosci.

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It is today widely accepted that several types of high molecular weight (MW) neurotransmitters produced by neurons are synthesized at the cell body, selectively stored within large dense core vesicles (LDCVs) and anterogradely transported to terminals where they elicit their biological role(s). Among these molecules there are neuropeptides and neurotrophic factors, the main focus of this perspective article. I here first provide a brief resume of the state of art on neuronal secretion, with primary emphasis on the molecular composition and mechanism(s) of filling and release of LDCVs. Then, I discuss the perspectives and future directions of research in the field as regarding the synthesis and storage of multiple high MW transmitters in LDCVs and the possibility that a selective sorting of LDCVs occurs along different neuronal processes and/or their branches. I also consider the ongoing discussion that diverse types of neurons may contain LDCVs with different sets of integral proteins or dial in a different fashion with LDCVs containing the same cargo. In addition, I provide original data on the size of LDCVs in rat dorsal root ganglion neurons and their central terminals in the spinal cord after immunogold labeling for calcitonin gene-related peptide (CGRP), neuropeptide K, substance P, neurokinin A or somatostatin. These data corroborate the idea that, similarly to endocrine cells, LDCVs undergo a process of maturation which involves a homotypic fusion followed by a reduction in size and condensation of cargo. They also give support to the conjecture that release at terminals occurs by cavicapture, a process of partial fusion of the vesicle with the axolemma, accompanied by depletion of cargo and diminution of size.

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Dense‐core vesicle biogenesis and exocytosis in neurons lacking chromogranins A and B

Abstract: Chromogranin A and B (Cgs) are considered to be master regulators of cargo sorting for the regulated secretory pathway (RSP) and dense-core vesicle (DCV) biogenesis.

Cited by 27 publications

References 46 publications

Chromogranin B regulates early-stage insulin granule trafficking from the Golgi in pancreatic islet β-cells

Chromogranin B regulates early-stage insulin granule trafficking from the Golgi in pancreatic islet β-cells

Chromogranin A in the early steps of the neurosecretory pathway

Costorage of High Molecular Weight Neurotransmitters in Large Dense Core Vesicles of Mammalian Neurons

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