Large dense-cored vesicle

Synaptic vesicles are the organelles in axon terminals that store neurotransmitters and release them by exocytosis. There are two types, the large dense-core vesicles, diameter about 90 nm, that contain neuropeptides, and the small synaptic vesicles, diameter about 50nm, that contain non-peptide transmitters. About ten vesicles per synapse are docked to the plasma membrane and ready for release, the readily releasable pool . Many more vesicles per synapse are stored farther away from the plasma membrane, the resting pool . When needed, the latter vesicles may be recruited into the readily releasable pool. Neuronal depolarization and activation of voltage-sensitive Ca2+... 

Figure 4.10 An electron micrograph of a terminal varicosity containing a large dense-core vesicle (LDCV), indicated by the arrow and many small synaptic vesicles (SSVs), some of which contain an electron dense core. Calibration mark 250 nM. (Figure kindly supplied by M. Fillenz)...

Neuropeptides are packaged into large, dense-core vesicles 325 Diversity is generated by families of propeptides, alternative splicing, proteolytic processing and post-translational modifications 326... 

The neuropeptides exhibit a few key differences from the classical neurotransmitters. First, neuropeptides are present in tissues at much lower concentrations than classical neurotransmitters. Consistent with this, neuropeptides are also active at receptors at correspondingly lower concentrations. For example, the concentration of ACh and NE in synaptic vesicles is in the 100-500 mmol/1 range, while the concentration of neuropeptide in a large dense core vesicle is 3-10 mmol/1 at most. Correspondingly, the affinity of ACh for its receptors is in the micromolar to millimolar range, while peptides typically bind to their receptors with affinities in the nanomolar to micromolar range. 

FIGURE 1 8-3 Intracellular pathway of bioactive peptide biosynthesis, processing and storage. Neuropeptide precursors are synthesized on ribosomes at the endoplasmic reticulum and processed through the Golgi. Axonal transport of the large dense-core vesicle to the synaptic site of release precedes the actual secretion. 

FIGURE18-4 Neuropeptides and conventional neurotransmitters are released from different parts of the nerve terminal. A neuromuscular junction containing both large dense-core vesicles (containing the neuropeptide SCP) and also small synaptic vesicles (containing acetylcholine) was stimulated for 30 min at 12 Hz (3.5 s every 7 s). Depletion of the small clear vesicles at the muscle face and of the peptide granules at the nonmuscle face of the nerve terminal was observed. After stimulation, there was an increase in the number of large dense-core vesicles within one vesicle diameter of the membrane. (Adapted from reference [37].)... 

FIGURE 18-11 Regulation of neuropeptide expression is exerted at several levels. ER, endoplasmic reticulum LDCV, large dense-core vesicle TGN, trans-Golgi network. 

FIGURE 18-12 The/af//af mutation in carboxypeptidase E (CPE) leads to secretion of proinsulin, not mature insulin, and results in diabetes. The S202P mutation within CPE results in degradation of the enzyme and defective insulin processing in the fat/fat heterozygous mouse. LDCV, large dense-core vesicle. 

LDCV large dense core vesicle MTI magnetization-transfer imaging... 

Figure 17.1. Neurotransmission (specific case of peptidergic cells). Production of the peptides in the cel I body (1). Packing of the peptides i nto large dense core vesicles for further transport to the axons (2). Release of neuropeptides from the cell soma (3) dendrites (4) and outside of the synapse (5). Release of classic neurotransmitters in the synaptic cleft (6). G-protein-coupled type receptors, which act as peptide receptors. (See color insert.)...

The terminals of cholinergic neurons contain large numbers of small membrane-bound vesicles concentrated near the synaptic portion of the cell membrane (Figure 6-3) as well as a smaller number of large dense-cored vesicles located farther from the synaptic membrane. The large vesicles contain a high concentration of peptide cotransmitters (Table 6-1), while the smaller clear vesicles contain most of the acetylcholine. Vesicles are initially synthesized in the neuron soma and transported to the terminal. They may also be recycled several times within the terminal. 

Neuropeptides are secreted by exocytosis of large dense-core vesicles (LDCVs) outside of synapses (Figure 1 Salio et al., 2006). LDCVs undergo exocytosis in all parts of a neuron, most often in axon terminals and dendrites. Monoamines are often co-stored with neuropeptides in LDCVs and co-secreted with them upon exocytosis. For all intents and purposes, LDCV-mediated secretion resembles hormone secretion in endocrine cells. 

Philos Trans R Soc Lond B Biol Sd 354 337-46 Khvotchev M, Lonart G, Sudhof TC (2000) Role of caldum in neurotransmitter release evoked by alpha-latrotoxin or hypertonic sucrose. Neuroscience 101 793-802 Klenchin VA, Kowalchyk JA, Martin TF (1998) Large dense-core vesicle exocytosis in PC12 cells. Methods 16 204-8... 

Pickel, V. M, Chan, J., Veznedaroglu, E., and Milner, T. A. (1995). Neuropeptide Y and dynorphin-immunoreactive large dense-core vesicles are strategically localized for presynaptic modulation in the hippocampal formation and substantia nigra. Synapse 19, 160-169. 

Tian J-H, Wu Z-X, Unzicker M, Lu L, Cai Q, et al. 2005. The role of snapin in neurosecretion Snapin knock-out mice exhibit impaired calcium-dependent exocytosis of large dense-core vesicles in chromaffin cells. J Neurosci 25 ... 

Local modulation through the dendritic release of DA occurs in both the SN and the VTA. Ultrastructural observations have been made with immunolocalization of the vesicular monoamine transporter-2 as marker for sites of intracellular monoamine storage within SN and VTA dopaminergic neurons identified by TH immunoreactivity (Nirenberg et al., 1996a). This study has reported that DA is stored in and may be released from dendritic small synaptic vesicles or large dense-core vesicles, while the smooth endoplasmic reticulum represents the main site for the DA storage. 

Catecholamines are stored in several types of vesicular granules that differ in size and type of protein and peptide components. In rat and bovine adrenal medulla there are two populations of chromaffin cells with morphologically distinct vesicles that preferentially store either norepinephrine or epinephrine and that release the two catecholamines differentially in response to different stimuli. In sympathetic nerves there are large and small dense core vesicles, the latter believed to be formed by retrieval of membranes of large dense core vesicles after exocytosis. ... 

Cozzi et al. (1989) and Munoz (1990) identified unipolar brush cells in the rat and human cerebellum, respectively, on the basis of their immunoreactivity to antisera against proteins of the secretogranin (or chromogranin) family. Unipolar brush have a relatively high density of large dense core vesicles, which in conjunction with the... 

The ultrastructure of NA fibers of the cerebellar cortex and other parts of the rat CNS was analyzed with pre-embedding dopamine-y5-hydroxylase immunohistochemistry by Olschowka et al. (1981). Immunoreaction product was present in the axoplasm, associated with smooth endoplasmatic reticulum, Golgi apparatus, synaptic and large dense core vesicles and the outer membranes of mitochondria. Large varicosities were interconnected by narrow intervaricose axon segments. Varicosities, filled with clear, round synaptic vesicles and large dark-core vesicles, made asymmetric contacts with dendrites, but never with somata or axons. More than 50% of the labelled varicosities in the cerebellum made synaptic contacts most of them with dendritic shafts, fewer on spines. 

A heterogeneous population of terminals, containing large dense-core vesicles with a diameter of 900 A, were found to be labelled in the cerebellar nuclei after intraventricular infusions of H-serotonin in the rat. Few of these boutons show synaptic specializations (Chan-Palay, 1975, 1977). The ultrastructural morphology of nor-... 

Of the antisera tested so far, those with the widest immunoreactivity across species and most commonly associated with neuromuscular locations (proximity of neurites to muscle) include pancreatic polypeptide-like peptide(s) (PP) of the neuropeptide Y (NPY) superfamily and Phe-Met-Arg-Phe-amide (FMRFamide)-like peptide(s), an invertebrate family of neuropeptides (22, 53, 55, 57, 61, 82, 89-92, 95, 103). In parasitic flatworms immunoreactivities to members of the NPY superfamily (neuropeptide Y, peptide YY and pancreatic polypeptide) and FMRFamide are likely to be largely or completely due to the native neuropeptide F (NPF) (22, 93, 100, 101). This 39 amino acid neuropeptide was first isolated and sequenced from the cestode Moniezia expansa and is viewed as a closely related member of the NPY superfamily it represents the first invertebrate member of this family to be isolated and sequenced. Similar staining patterns for the PP and PYY members of the NPY superfamily, FMRFamide and NPF have been obtained. Ultrastructural studies have co-localized NPF, PP and FMRFamide to a specific population of large dense-core vesicles in neurons of some species. NPF quenches PP and FMRFamide immunoreactivities but not vice versa. These results obtained in species of trematodes and cestodes suggest that most, if not all, of the... 

Engisch KL, Nowycky MC. Calcium dependence of large dense-cored vesicle exocytosis evoked by calcium influx in bovine adrenal chromaffin cells. J Neurosci 1996 16(4) 1359-69. 

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