A5028591204- Cellular transport and secretion
- Receptor Mechanisms and Signaling
- Neuropeptides and Animal Physiology
- Biochemical and Structural Characterization
- Lipid Membrane Structure and Behavior
- Biotin and Related Studies
- Nicotinic Acetylcholine Receptors Study
- Neuroinflammation and Neurodegeneration Mechanisms
- Retinoids in leukemia and cellular processes
- Pancreatic function and diabetes
- Neuroscience and Neuropharmacology Research
- Adipose Tissue and Metabolism
- Antimicrobial Peptides and Activities
- Peptidase Inhibition and Analysis
- Adenosine and Purinergic Signaling
- Renin-Angiotensin System Studies
- Retinal Development and Disorders
- Alzheimer's disease research and treatments
- Hormonal Regulation and Hypertension
- Protease and Inhibitor Mechanisms
- Genetic Associations and Epidemiology
- Antioxidant Activity and Oxidative Stress
- Circadian rhythm and melatonin
- Diet and metabolism studies
- Photoreceptor and optogenetics research
University of California, San Diego
2004-2013
VA San Diego Healthcare System
2002-2013
Center for Human Genetics
2007-2010
University of Montana
2010
Uppsala University
2008-2009
Max Planck Institute of Molecular Cell Biology and Genetics
2009
University of Milan
2009
QIMR Berghofer Medical Research Institute
2008
University of Southern California
2007-2008
Buck Institute for Research on Aging
2003
Catecholamine secretory vesicle core proteins (chromogranins) contain an activity that inhibits catecholamine release, but the identity of responsible peptide has been elusive. Size-fractionated chromogranins antagonized nicotinic cholinergic-stimulated secretion; inhibitor was enriched in processed chromogranin fragments, and liberated from purified A. Of 15 synthetic peptides spanning approximately 80% A, one (bovine A344-364 [RSMRLSFRARGYGFRGPGLQL], or catestatin) a potent, dose-dependent...
Chromogranins constitute a family of acidic soluble proteins widely distributed in endocrine cells and neurons. Chromogranin A, the major component bovine adrenal medullary secretory granules chromaffin cells, has been shown to be actively processed peptide fragments [Metz-Boutigue, M. H., Garcia-Sablone, P., Hogue-Angeletti, R. & Aunis, D. (1993) Eur. J. Biochem. 217, 247-257]. In present paper, structural features proteolytic degradation mechanism chromogranin B/secretogranin I have...
Chromogranin A (CGA) belongs to a multifunctional protein family widely distributed in secretory vesicles neurons and neuroendocrine cells. Within the brain, CGA is localized neurodegenerative areas associated with reactive microglia. By using cultured rodent microglia, we recently described that induces an activated phenotype generation of nitric oxide. These findings led us examine whether might affect neuronal survival, expression neurofilaments, high affinity γ-aminobutyric acid uptake...
Background— Tyrosine hydroxylase (TH) is the rate-limiting enzyme in catecholamine biosynthesis. Does common genetic variation at human TH alter autonomic activity and predispose to cardiovascular disease? We undertook systematic polymorphism discovery locus then tested variants for contributions sympathetic function blood pressure. Methods Results— resequenced 80 ethnically diverse individuals across locus. One hundred seventy-two twin pairs were evaluated traits, including production,...
Background— Chromogranin A (CHGA) triggers catecholamine secretory granule biogenesis, and its catestatin fragment inhibits release. We approached heritability using twin pairs, coupled with genome-wide linkage, in a series of sibling pairs from 2 continents. Methods Results— Hypertensive patients had elevated CHGA reduction catestatin, suggesting diminished conversion precursor to catestatin. Heritability for twins was 44% 60%. Six hundred fifteen nuclear families yielded 870 sib...
Chromogranin A (CgA), the major soluble protein in chromaffin granules, is proteolytically processed to generate biologically active peptides including catecholamine release inhibitory peptide catestatin. Here we sought determine whether cysteine protease cathepsin L (CTSL), a novel enzyme for proteolytic processing of neuropeptides, acts like well-established serine proteases [prohormone convertase (PC)1/3 or PC2] catestatin by CgA. We found that endogenous CTSL colocalizes with CgA...
Chromogranins constitute a family of acidic soluble proteins widely distributed in endocrine cells and neurons. Chromogranin A, the major component bovine adrenal medullary secretory granules chromaffin cells, has been shown to be actively processed peptide fragments [Metz-Boutigue, M. H., Garcia-Sablone, P., Hogue-Angeletti, R. & Aunis, D. (1993) Eur. J. Biochem. 217, 247–257]. In present paper, structural features proteolytic degradation mechanism chromogranin B/secretogranin I have...
The chromogranin A (CHGA) fragment pancreastatin (human CHGA250-301) impairs glucose metabolism, but the role of human in vivo remains unexplored.We studied brachial arterial infusion (CHGA273-301-amide at approximately 200 nm) on forearm metabolism glucose, free fatty acids, and amino acids. Plasma was measured obesity or type 2 diabetes. Systematic discovery acid variation performed, potency one variant active carboxyl terminus (Gly297Ser) tested.Pancreastatin decreased uptake by 48-50%;...
The constitutive and regulated secretory pathways represent the classical routes for secretion of proteins from neuroendocrine cells. Selective aggregation granule constituents in an acidic, bivalent cation-rich environment is considered to be a prerequisite sorting pathway. effect selective vacuolar H+-ATPase (V-ATPase) inhibitor bafilomycin A1 on pH gradient along pathway was used here study role acidification trafficking protein chromogranin A (CgA) PC12 Sorting CgA assessed by...
Tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis, has a common tetranucleotide repeat polymorphism, (TCAT)(n). We asked whether variation at (TCAT)(n) may influence autonomic nervous system and its response to environmental stress. To understand role of heredity such traits, we turned human twin study design. Both biochemical physiological traits displayed substantial heritability (h(2)), up h(2) = 56.8 +/- 7.5% (P < 0.0001) for norepinephrine secretion, 61 6%...
Hypertension is a common hereditary syndrome with unclear pathogenesis. Chromogranin A (Chga), which catalyzes formation and cargo storage of regulated secretory granules in neuroendocrine cells, contributes to blood pressure homeostasis centrally peripherally. Elevated Chga occurs spontaneously hypertensive rat (SHR) adrenal glands plasma, but central expression unexplored. In this report, we measured SHR Wistar–Kyoto (control) peripheral nervous systems, found protein be decreased the...
Chromogranin A (CgA), the major soluble protein in catecholamine storage vesicles, serves as a prohormone that is cleaved into bioactive peptides inhibit release, providing an autocrine, negative feedback mechanism for regulating responses during stress. However, proteases responsible processing of CgA and release have not been established. Recently, we found chromaffin cells express components plasmin(ogen) system, including tissue plasminogen activator, which targeted to vesicles released...
Chromogranin A (CgA) is the index member of chromogranin/secretogranin(or `granin') family regulated secretory proteins that are ubiquitously distributed in amine- and peptide-containing granules endocrine,neuroendocrine neuronal cells. Because their abundance such widespread occurrence, granins have often been used as prototype to elucidate mechanisms protein targeting into dense-core granules. In this study, we a series full-length, point mutant or truncated CgA-green fluorescent (GFP)...
The catestatin fragment of chromogranin A is an inhibitor catecholamine release, but its occurrence in vivo has not yet been verified, nor have precise cleavage sites established. Here we found extensive processing A, as judged by radioimmunoassay size-fractionated chromaffin granules. On mass spectrometry, a major form was bovine A332–364; identity the peptide confirmed diagnostic Met346oxidation. Further analysis revealed two additional forms: A333–364 and A343–362. Synthetic longer...
Pituitary adenylyl cyclase-activating polypeptide (PACAP) is a potent endogenous secretagogue for chromaffin cells. Chromogranin A the major soluble core component in secretory vesicles. Since chromogranin secreted along with catecholamines, we asked whether PACAP regulates expression of gene PC12 rat cells, so as to resynthesize just-secreted protein, and such biosynthetic regulation coupled mechanistically catecholamine secretion. activated by four- fivefold. Proportional results (seven-...
We have employed amoeboid microglia purified from primary cultures of neonatal rat brain to examine the effect bacterial lipopolysaccharide (LPS), a potent activator immune cells, on intracellular calcium concentration ([Ca2+]i) in macrophages. In single macrophages loaded with indo 1, pulse administration LPS elicited rapid and transient increase [Ca2+]i. From total 70 cells examined, all responded similar [Ca2+]i transient, indicating good homogeneity cell population regard response. It...
Rationale Dopamine beta-hydroxylase (DBH) plays an essential role in catecholamine synthesis by converting dopamine into norepinephrine. Here we systematically investigated DBH polymorphisms associated with enzymatic activity as well autonomic and blood pressure (BP)/disease phenotypes vivo. Methods results Seventy genetic variants were discovered at the locus; across ethnicities, much of promoter was spanned a 5' haplotype block, larger block spanning whites than blacks. secretion predicted...
Secretogranin II (SgII) belongs to the granin family of prohormones widely distributed in dense-core secretory granules (DCGs) endocrine, neuroendocrine, and neuronal cells, including sympathoadrenal chromaffin cells. The mechanisms by which proteins, granins particular, are sorted into regulated pathway unsettled. We designed a strategy based on novel chimeric forms human SgII fused fluorescent (green protein) or chemiluminescent (embryonic alkaline phosphatase) reporters identify...
Processes underlying the formation of dense core secretory granules (DCGs) neuroendocrine cells are poorly understood. Here, we present evidence that DCG biogenesis is dependent on protein secretogranin (Sg) II, a member granin family pro-hormone cargo DCGs in cells. Depletion SgII expression PC12 leads to decrease both number and size impairs trafficking other regulated hormones. Expression fusion proteins secretory-deficient variant rescues pathway. SgII-containing vesicles share...
Abstract —Pituitary adenylyl cyclase-activating polypeptide (PACAP) is a potent endogenous secretagogue for chromaffin cells. We previously reported that PACAP coupled to the PAC1 receptor evoke dihydropyridine-sensitive early (15 20 minutes) catecholamine secretion and cAMP response element binding protein–mediated trans- activation of secretory protein chromogranin A promoter in PC12 pheochromocytoma In this report, we studied whether transcriptional responses elicited by were subject...
To explore stimulus-transcription coupling in pheochromocytoma cells, we studied the biosynthetic response of chromogranin A, major soluble protein co-stored and co-released with catecholamines, to chromaffin cells' physiologic nicotinic cholinergic secretory stimulation. Chromogranin A mRNA showed a time-dependent 3.87-fold stimulation, nuclear run-off experiment indicated that occurred at transcriptional level. Transfected promoter/luciferase reporter constructs were activated by time-...