C-terminal Domain of Chromogranin B Regulates Intracellular Calcium Signaling

Schmidt, Stefan; Mo, Michelle; Heidrich, Felix M.; Ćelić, Andjelka; Ehrlich, Barbara E.

doi:10.1074/jbc.m111.251330

Cited by 11 publications

(13 citation statements)

References 22 publications

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“…Our study demonstrates that in symptomatic EAE mice, a dramatic accumulation of CGB occurs. This increase in CGB likely contributes to the elevation of cytosolic calcium levels, as demonstrated by prior studies (Choe et al, 2004; Jacob et al, 2005; Schmidt et al, 2011). The elevation in cytosolic calcium then turns on calcium dependent proteases, namely, calpain.…”

Section: Discussionsupporting

confidence: 60%

“…It was previously found that in areas with little InsP3R, CGB levels are elevated to compensate for the decreased InsP3R expression (Nicolay et al, 2007). Additionally, subcellular changes in intracellular CGB expression lead to significantly altered calcium release kinetics and calcium signal initiation sites (Choe et al, 2004; Jacob et al, 2005; Schmidt et al, 2011). For instance, overexpression of CGB causes an increase in InsP3R mediated-calcium release.…”

Section: Resultsmentioning

confidence: 99%

“…In a healthy neuron (Figure 9a), CGB facilitates the formation of secretory vesicles (Chanat et al, 1993; Schmidt et al, 2011), is ubiquitinated, is secreted, and positively modulates the activity of the InsP3R (Choe et al, 2004). CGB also alters cellular calcium kinetics such as peak calcium release, total calcium release, and calcium signal initiation sites (Choe et al, 2004; Jacob et al, 2005; Schmidt et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…CGB also alters cellular calcium kinetics such as peak calcium release, total calcium release, and calcium signal initiation sites (Choe et al, 2004; Jacob et al, 2005; Schmidt et al, 2011). …”

Section: Discussionmentioning

confidence: 99%

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The role of chromogranin B in an animal model of multiple sclerosis

Hoang

Schmidt

et al. 2013

Molecular and Cellular Neuroscience

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Chromogranin B (CGB) is a high capacity, low affinity calcium binding protein in the endoplasmic reticulum (ER) that binds to the inositol 1,4,5 trisphosphate receptor (InsP3R) and amplifies calcium release from ER stores. Recently, it was discovered that levels of CGB-derived peptides are decreased in the cerebrospinal fluid of multiple sclerosis (MS) patients. One of the mechanisms by which neurodegeneration in MS is thought to occur is through increased levels of intra-axonal calcium. The combination of excess intracellular calcium and dysregulated levels of CGB in MS led us to hypothesize that CGB may be involved in MS pathophysiology. Here, we show in a mouse model of MS that CGB levels are elevated in neurons prior to onset of symptoms. Once symptoms develop, CGB protein levels increase with disease severity. Additionally, we show that elevated levels of CGB may have a role in the pathophysiology of MS and suggest that the initial elevation of CGB, prior to symptom onset, is due to inflammatory processes. Upon development of symptoms, CGB accumulation in neurons results from decreased ubiquitination and decreased secretion. Furthermore, we show that calpain activity is increased and levels of InsP3R are decreased. From these results, we suggest that the elevated levels of CGB and altered InsP3R levels may contribute to the axonal/neuronal damage and dysregulated calcium homeostasis observed in MS. Additionally, we propose that CGB can be a biomarker that predicts the onset and severity of disease in patients with MS.

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Section: Discussionsupporting

confidence: 60%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The role of chromogranin B in an animal model of multiple sclerosis

Hoang

Schmidt

et al. 2013

Molecular and Cellular Neuroscience

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“…In particular, three studies tried to investigate the potential role of the polymorphism c.1238CNT in exon 4 of the CHGB gene in different ALS populations Van Vught et al, 2010;Blasco et al, 2011). This SNP is located in the C-terminal region of CgB, crucial for inducing calcium release (Schmidt et al, 2011), but not within or in proximity of the known binding site to mutant SOD1, located in a Hsp-like domain (region 162-285) . Moreover, the region containing the variation has not been conserved during evolution , suggesting that the functional role for this region could be limited.…”

Section: Discussionmentioning

confidence: 99%

Lack of relationship between the P413L chromogranin B variant and a SALS Italian cohort

Ricci

Battistini

Avemaria

et al. 2015

Gene

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Quantitative proteomics suggests decrease in the secretogranin‐1 cerebrospinal fluid levels during the disease course of multiple sclerosis

et al. 2015

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Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS with unknown cause. Proteins with different abundance in the cerebrospinal fluid (CSF) from relapsing-remitting MS (RRMS) patients and neurological controls could give novel insight to the MS pathogenesis and be used to improve diagnosis, predict prognosis and disease course, and guide in therapy decisions. We combined iTRAQ labeling and Orbitrap mass spectrometry to discover proteins with different CSF abundance between six RRMS patients and 18 neurological disease controls. From 777 quantified proteins seven were selected as biomarker candidates, namely chitinase-3-like protein 1, secretogranin-1 (Sg1), cerebellin-1, neuroserpin, cell surface glycoprotein MUC18, testican-2 and glutamate receptor 4. An independent sample set of 13 early-MS patients, 13 RRMS patients and 13 neurological controls was used in a multiple reaction monitoring verification study. We found the intracellular calcium binding protein Sg1 to be increased in early-MS patients compared to RRMS and neurological controls. Sg1 should be included in further studies to elucidate its role in the early phases of MS pathogenesis and its potential as a biomarker for this disease.

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C-terminal Domain of Chromogranin B Regulates Intracellular Calcium Signaling

Cited by 11 publications

References 22 publications

The role of chromogranin B in an animal model of multiple sclerosis

The role of chromogranin B in an animal model of multiple sclerosis

Lack of relationship between the P413L chromogranin B variant and a SALS Italian cohort

Quantitative proteomics suggests decrease in the secretogranin‐1 cerebrospinal fluid levels during the disease course of multiple sclerosis

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