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Chromogranin B (CHGB) is the major matrix protein in human catecholamine storage vesicles. CHGB genetic variation alters catecholamine secretion and blood pressure. Here, effective Chgb protein under-expression was achieved by siRNA in PC12 cells, resulting in ~ 48% fewer secretory granules on electron microscopy, diminished capacity for catecholamine uptake (by ~ 79%), and a ~ 73% decline in stores available for nicotinic cholinergic-stimulated secretion. In vivo, loss of Chgb in knockout mice resulted in a ~ 35% decline in chromaffin granule abundance and ~ 44% decline in granule diameter, accompanied by unregulated catecholamine release into plasma. Over-expression of CHGB was achieved by transduction of a CHGB-expressing lentivirus, resulting in ~ 127% elevation in CHGB protein, with ~ 122% greater abundance of secretory granules, but only ~ 14% increased uptake of catecholamines, and no effect on nicotinic-triggered secretion. Human CHGB protein and its proteolytic fragments inhibited nicotinic-stimulated catecholamine release by ~ 72%. One conserved-region CHGB peptide inhibited nicotinic-triggered secretion by up to ~ 41%, with partial blockade of cationic signal transduction. We conclude that bi-directional quantitative derangements in CHGB abundance result in profound changes in vesicular storage and release of catecholamines. When processed and released extra-cellularly, CHGB proteolytic fragments exert a feedback effect to inhibit catecholamine secretion, especially during nicotinic cholinergic stimulation. Here, we show reciprocal actions of Chromogranin B (CHGB) on catecholamine storage (stimulation) and release (inhibition). The figure synthesizes consequences of experimental results. Within chromaffin cells, CHGB participates in assembly of catecholamine secretory vesicles, and governs their secretory capacity under nicotinic stimulation. After cleavage and release into the extracellular space, CHGB [and its peptide hCHGB[60-67](KFEVRLLR)] exerts negative feedback effects to inhibit the secretory response to acetylcholine (ACh).
Zhang K, Biswas N, Gayen JR et al., J Neurochem. 2013 Nov 8. doi: 10.1111/jnc.12527. [Epub ahead of print]
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BACKGROUND:
Bipolar disorder is a common psychiatric mood disorder that is defined by recurrent episodes of abnormally elevated mood and depression. Progressive structural brain changes in individuals with bipolar disorder have been suggested to be associated with defects in the secretion of neurotrophic factors. We sought to assess how the regulated secretory pathway in the brain is affected in patients with bipolar disorder by measuring chromogranin B and secretogranin II, which are 2 cerebrospinal fluid (CSF) biological markers for this process.
METHODS:
We measured the concentrations of chromogranin B (peptide 439-451) and secretogranin II (peptide 154-165) in the CSF of patients with well-defined bipolar disorder and healthy controls. The lifetime severity of bipolar disorder was rated using the Clinical Global Impression (CGI) scale.
RESULTS:
We included 126 patients with bipolar disorder and 71 healthy controls in our analysis. Concentrations of secretogranin II were significantly lower in patients with bipolar disorder type I than in healthy controls. The reduction was most pronounced in patients with high CGI scores (i.e., severe disease).
LIMITATIONS:
The cross-sectional design of the current study limits the ability to pinpoint the causalities behind the observed associations.
CONCLUSION:
This study shows that the CSF marker secretogranin II has the potential to act as a biological marker for severe forms of bipolar disorder. Our findings indicate that patients with bipolar disorder possess defects in the regulatory secretory pathway, which may be of relevance to the progressive structural brain changes seen in those with severe forms of the disease.
Jakobsson J, Stridsberg M, Zetterberg H et al., J Psychiatry Neurosci. 2013 Jul;38(4):E21-6. doi: 10.1503/jpn.120170.
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Marksteiner J at el. J Mol Neurosci. 2002 Feb-Apr;18(1-2):53-63.
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Chromogranin A, chromogranin B, and secretogranin II are acidic
proteins which are stored in large dense core vesicles of neurons. An
antiserum, raised against a synthetic peptide (PE-11), present in the
chromogranin B molecule, and an antiserum raised against secretoneurin
contained in the secretogranin II sequence, was used to localize these
peptides together with chromogranin A in the human hippocampal
formation. The distribution of these peptides was investigated in
Alzheimer's disease and compared to control subjects. Chromogranin A,
chromogranin B, and secretogranin II are distinctly distributed with an
overlap in their distribution patterns. They were only detected in
neuronal structures. The highest density of immunoreactivity was found
for chromogranin B. A layer specific distribution was especially obvious
in the inner molecular layer of the dentate gyrus as secretoneurin-like
immunoreactivity was restricted to its innermost part whereas that of
chromogranin B was highly concentrated throughout the inner molecular
layer. In Alzheimer's disease, about 10 to 20% of the
amyloid-immunoreactive plaques contained either chromogranin A,
chromogranin B or secretoneurin. The density of secretoneurin-and
chromogranin B-like immunoreactivity was significantly reduced in the
inner molecular layer of the dentate gyyrs, the CA1 area, the subiculum
and in layers I, III and V of the entorhinal cortex. The present study
demonstrates that chromogranin peptides are markers for human
hippocampal pathways. Thee are particularly suitable to study nerve
fibers, terminating at the inner molecular layer of the dentate gyrus.
Chromogranin peptides have a potential as neuronal markers for synaptic
degeneration in Alzheimer's disease.
Marksteiner J at el. J Mol Neurosci. 2002 Feb-Apr;18(1-2):53-63.
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Lechner T at el. Exp Gerontol. 2004 Jan;39(1):101-13.
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Synaptic disturbances may play a key role in the pathophysiology of
Alzheimer's disease. To characterize differential synaptic alterations
in the brains of Alzheimer patients, chromogranin A, chromogranin B and
secretoneurin were applied as soluble constituents for large dense core
vesicles, synaptophysin as a vesicle membrane marker and calbindin as a
cytosolic protein. In controls, chromogranin B and secretogranin are
largely co-contained in interneurons, whereas chromogranin A is mostly
found in pyramidal neurons. In Alzheimer's disease, about 30% of
beta-amyloid plaques co-labelled with chromogranin A, 20% with
secretoneurin and 15% with chromogranin B. Less than 5% of beta-amyloid
plaques contained synaptophysin or calbindin, respectively.
Semiquantitative immunohistochemistry revealed a significant loss for
chromogranin B- and secretoneurin-like immunoreactivity in the
dorsolateral, the entorhinal, and orbitofrontal cortex. Chromogranin A
displayed more complex changes. It was the only chromogranin peptide to
be expressed in glial fibrillary acidic protein containing cells. About
40% of chromogranin A immunopositive plaques and extracellular deposits
were surrounded and pervaded by activated microglia. The present study
demonstrates a loss of presynaptic proteins involved in distinct steps
of exocytosis. An imbalanced availability of chromogranins may be
responsible for impaired neurotransmission and a reduced functioning of
dense core vesicles. Chromogranin A is likely to be a mediator between
neuronal, glial and inflammatory mechanisms found in Alzheimer disease.
Lechner T at el. Exp Gerontol. 2004 Jan;39(1):101-13.
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Mattsson N at el. J Alzheimers Dis. 2010;20(4):1039-49.
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Much is unknown regarding the regulation of Alzheimer-related
amyloid-beta protein precursor (AbetaPP)-processing in the human central
nervous system. It has been hypothesized that amyloidogenic
AbetaPP-processing preferentially occurs in the regulated secretory
pathway of neurons. To test this hypothesis we looked for correlations
of AbetaPP-derived molecules in cerebrospinal fluid (CSF) with
chromogranin (Cg) derived peptides, representing the regulated
secretion. Patients with Alzheimer's disease (AD, N=32), multiple
sclerosis (MS, N=50), and healthy controls (N= 70) were enrolled. CSF
was analyzed for the amyloid peptides Abeta1-42, Abetax-42, Abetax-40,
Abetax-38, alpha-cleaved soluble AbetaPP (sAbetaPPalpha), beta-cleaved
soluble AbetaPP (sAbetaPPbeta), and peptides derived from CgB and SgII
(Secretogranin-II, CgC). We investigated CSF levels of the protease
BACE1, which processes AbetaPP into Abeta, in relation to Cg-levels.
Finally, we measured Cg levels in cell media from untreated and
BACE1-inhibited SH-SY5Y human neuroblastoma cells. CSF Cg levels
correlated to sAbetaPP and Abeta peptides in AD, MS, and controls, and
to CSF BACE1. Cell medium from BACE1-inhibited cells had decreased CgB
levels. These results suggest that a large part of AbetaPP in the human
central nervous system is processed in the regulated secretory pathway
of neurons.
Mattsson N at el. J Alzheimers Dis. 2010;20(4):1039-49.
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Willis M at el. J Alzheimers Dis. 2008 Mar;13(2):123-35.
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Chromogranin B and secretogranin II are major soluble constituents of
large dense core vesicles of presynaptic structures and have been found
in neuritic plaques of Alzheimer patients. We examined the distribution
and expression of these peptides in both transgenic mice over expressing
human amyloid-beta protein precursor APP751 with the London (V717I) and
Swedish (K670M/N671L) mutations and in human post-mortem brain. In
transgenic mice, the number of amyloid-beta plaques and chromogranin
immunopositive plaques increased from 6 to 12 months. About 60% of
amyloid-beta plaques were associated with chromogranin B and about 40%
with secretogranin II. Chromogranin immunoreactivity appeared mainly as
swollen dystrophic neurites. Neither synaptophysin- nor glial fibrillary
acidic protein- immunoreactivity was expressed in chromogranin
immunoreactive structures at any timepoint. Density of chromogranin
peptides in hippocampal structures did not change in transgenic animals
at any timepoint, even though animals had a poorer performance in the
Morris water maze task. In conclusion, our findings in transgenic
animals partly resembled findings in Alzheimer patients. Chromogranin
peptides were associated with amyloid-beta plaques, but were not reduced
in specific brain areas as previously reported by our group. Therefore
specific changes of chromogranin peptides observed in Alzheimer patients
can be related to amyloid-beta pathology only.
Willis M at el. J Alzheimers Dis. 2008 Mar;13(2):123-35.
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In the endocrine pancreas, chromogranin-A and pancreastatin have been suggested to inhibit islet insulin secretion, whereas chromogranin-B has not been studied in this context. Furthermore, a putative effect by chromogranins on IAPP secretion is unknown. We aimed to elucidate the endogenous effect of chromogranin-A, pancreastatin and chromogranin-B on islet insulin and IAPP secretion from pancreatic NMRI mouse islets. In acute experiments, there was a tendency towards an increase in insulin release, which became more manifest after a 48-h exposure. Moreover, 48 h exposure to chromogranin-B antiserum resulted in a significant increase in (pro)insulin synthesis. Neither antibodies against chromogranin-A nor pancreastatin had any effect on islet hormone secretion. None of the antibodies tested had any effect on islet IAPP or insulin content. We suggest that chromogranin-B released from islets may have an autocrine inhibitory effect on islet IAPP and insulin secretion. Our data imply a regulatory role of chromogranin-B in islet IAPP and insulin secretion.
Karlsson E, Stridsberg M, Sandler S, Regul Pept. 2000 Feb 8;87(1-3):33-9.
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VGF;NERP-2-TLQP-62;NERP_3_4;TLQP21;AQEE-30;VGF 373-417;Secretoneurin;Manserin
%Chromogranin B%;%VGF%;%NERP%;%TLQP%;%AQEE%;%secretoneurin%;%secretogranin%;%EM-66%;%manserin%
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