Abstract
Secretory vesicles are required for release of chemical messengers to mediate intercellular signaling among human biological systems. It is necessary to define the organization of the protein architecture of the ‘human’ dense core secretory vesicles (DCSV) to understand mechanisms for secretion of signaling molecules essential for cellular regulatory processes. This study, therefore, conducted extensive quantitative proteomics and systems biology analyses of human DCSV purified from human pheochromocytoma. Over 600 human DCSV proteins were identified with quantitative evaluation of over 300 proteins, revealing that most proteins participate in producing peptide hormones and neurotransmitters, enzymes, and the secretory machinery. Systems biology analyses provided a model of interacting DCSV proteins, generating hypotheses for differential intracellular protein kinases A and C signaling pathways. Activation of cellular PKA and PKC pathways resulted in differential secretion of neuropeptides, catecholamines, and β-amyloid of Alzheimer's disease for mediating cell-cell communication. This is the first study to define a model of the protein architecture of human DCSV for human disease and health.
Highlights
The secretory vesicle organelle is essential for regulated release of chemical messengers that mediate cell-cell communication in the control of biological functions in human health and disease [1,2,3]
A hypothesis of the model was experimentally evaluated to assess the roles of protein kinases A and C (PKA and protein kinase C (PKC), respectively) in regulating secretion of dense core secretory vesicles (DCSV) chemical messengers consisting of neuropeptides, catecholamines, and beta-amyloid
This report represents the most comprehensive study of the protein architecture of human dense core secretory vesicles (DCSV), which are critical for regulating neuroendocrine intercellular signaling in human health and disease
Summary
The secretory vesicle organelle is essential for regulated release of chemical messengers that mediate cell-cell communication in the control of biological functions in human health and disease [1,2,3]. Recent advances in mass spectrometry [8,9] and systems biology [10] provide the basis of this study to define the proteome of human DCSV isolated from the human sympathoadrenal system. These studies were designed to answer two important questions. What proteins comprise ‘human’ DCSV and what are their relative quantities? Secondly, what functional organization and protein networks exist among proteins comprising ‘human’ DCSV? definition of the human DCSV proteome data is a necessary resource to guide biological studies in model organisms to elucidate DCSV functions that are relevant to human physiological functions
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