title: Impact of Chromogranin A deficiency on catecholamine storage, catecholamine granule morphology and chromaffin cell energy metabolism in vivo.
abstract: Chromogranin A (CgA) is a prohormone and granulogenic factor in neuroendocrine tissues with a regulated secretory pathway. The impact of CgA depletion on secretory granule formation has been previously demonstrated in cell culture. However, studies linking the structural effects of CgA deficiency with secretory performance and cell metabolism in the adrenomedullary chromaffin cells in vivo have not previously been reported. Adrenomedullary content of the secreted adrenal catecholamines norepinephrine (NE) and epinephrine (EPI) was decreased 30-40 % in Chga-KO mice. Quantification of NE and EPI-storing dense core (DC) vesicles (DCV) revealed decreased DCV numbers in chromaffin cells in Chga-KO mice. For both cell types, the DCV diameter in Chga-KO mice was less (100-200 nm) than in WT mice (200-350 nm). The volume density of the vesicle and vesicle number was also lower in Chga-KO mice. Chga-KO mice showed an ~47 % increase in DCV/DC ratio, implying vesicle swelling due to increased osmotically active free catecholamines. Upon challenge with 2 U/kg insulin, there was a diminution in adrenomedullary EPI, no change in NE and a very large increase in the EPI and NE precursor dopamine (DA), consistent with increased catecholamine biosynthesis during prolonged secretion. We found dilated mitochondrial cristae, endoplasmic reticulum and Golgi complex, as well as increased synaptic mitochondria, synaptic vesicles and glycogen granules in Chga-KO mice compared to WT mice, suggesting that decreased granulogenesis and catecholamine storage in CgA-deficient mouse adrenal medulla is compensated by increased VMAT-dependent catecholamine update into storage vesicles, at the expense of enhanced energy expenditure by the chromaffin cell.
authors.affiliation: Department of Medicine, University of California - San Diego, San Diego, CA, USA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Pasqua
authors.affiliation: California Institute of Technology, Pasadena, CA, USA.
authors.forename: Sumana
authors.initials: S
authors.lastname: Mahata
authors.affiliation: Department of Medicine, University of California - San Diego, San Diego, CA, USA.
authors.forename: Gautam K
authors.initials: GK
authors.lastname: Bandyopadhyay
authors.affiliation: Department of Medicine, University of California - San Diego, San Diego, CA, USA.
authors.forename: Angshuman
authors.initials: A
authors.lastname: Biswas
authors.affiliation: National Center for Microscopy and Imaging Research, San Diego, CA, USA.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Perkins
authors.affiliation: Charles Drew University of Medicine and Science, Los Angeles, CA, USA.|David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
authors.forename: Amiya P
authors.initials: AP
authors.lastname: Sinha-Hikim
authors.affiliation: Clinical Neurocardiology Section, NINDS-IRP, Bethesda, MD, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Goldstein
authors.affiliation: Section on Molecular Neuroscience, NIMH-IRP, Bethesda, MD, USA.
authors.forename: Lee E
authors.initials: LE
authors.lastname: Eiden
authors.affiliation: Department of Medicine, University of California - San Diego, San Diego, CA, USA. smahata@ucsd.edu.|VA San Diego Healthcare System, San Diego, CA, USA. smahata@ucsd.edu.|Metabolic Physiology & Ultrastructural Biology Laboratory, Department of Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0732, USA. smahata@ucsd.edu.
authors.forename: Sushil K
authors.initials: SK
authors.lastname: Mahata
mesh_terms: D000311:Adrenal Glands / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002395:Catecholamines / Q000378:metabolism*; D002837:Chromaffin Granules / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D053379:Chromogranin A / Q000172:deficiency* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000648:ultrastructure; D004734:Energy Metabolism / Q000187:drug effects; D004837:Epinephrine / Q000378:metabolism; D005089:Exocytosis / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D013153:Splanchnic Nerves / Q000187:drug effects / Q000378:metabolism; D013572:Synaptic Vesicles / Q000187:drug effects / Q000378:metabolism
chemical_list: D002395:Catecholamines; D053379:Chromogranin A; D007328:Insulin; D006003:Glycogen; D005947:Glucose; D004298:Dopamine; D009638:Norepinephrine; D004837:Epinephrine
keywords: Dense core vesicle; Epinephrine; Mitochondria; Norepinephrine; Synaptic vesicle