ACS Publications. Most Trusted. Most Cited. Most Read
My Activity

Figure 1Loading Img

Proteomics of Dense Core Secretory Vesicles Reveal Distinct Protein Categories for Secretion of Neuroeffectors for Cell−Cell Communication

View Author Information
Skaggs School of Pharmacy and Pharmaceutical Sciences, Departments of Pediatrics, Cellular and Molecular Medicine, Pathology, Medicine, and Neurosciences, School of Medicine, University of California, San Diego, La Jolla, California 92093
* To whom correspondence should be addressed. Vivian Hook, Ph.D., School of Pharmacy, Univ. of Calif, San Diego, 9500 Gilman Dr. MC 0744, La Jolla, CA 92093, phone (858) 822-6682, e-mail: [email protected]
†The first two authors contributed equal and significant efforts to this study.
‡Skaggs School of Pharmacy and Pharmaceutical Sciences.
§Departments of Pediatrics and Cellular and Molecular Medicine.
∥Department of Pathology.
⊥Department of Medicine.
#Department of Neurosciences and Medicine.
Cite this: J. Proteome Res. 2010, 9, 10, 5002–5024
Publication Date (Web):August 9, 2010
Copyright © 2010 American Chemical Society

    Article Views





    Other access options
    Supporting Info (3)»


    Abstract Image

    Regulated secretion of neurotransmitters and neurohumoral factors from dense core secretory vesicles provides essential neuroeffectors for cell−cell communication in the nervous and endocrine systems. This study provides comprehensive proteomic characterization of the categories of proteins in chromaffin dense core secretory vesicles that participate in cell−cell communication from the adrenal medulla. Proteomic studies were conducted by nano-HPLC Chip MS/MS tandem mass spectrometry. Results demonstrate that these secretory vesicles contain proteins of distinct functional categories consisting of neuropeptides and neurohumoral factors, protease systems, neurotransmitter enzymes and transporters, receptors, enzymes for biochemical processes, reduction/oxidation regulation, ATPases, protein folding, lipid biochemistry, signal transduction, exocytosis, calcium regulation, as well as structural and cell adhesion proteins. The secretory vesicle proteomic data identified 371 proteins in the soluble fraction and 384 membrane proteins, for a total of 686 distinct secretory vesicle proteins. Notably, these proteomic analyses illustrate the presence of several neurological disease-related proteins in these secretory vesicles, including huntingtin interacting protein, cystatin C, ataxin 7, and prion protein. Overall, these findings demonstrate that multiple protein categories participate in dense core secretory vesicles for production, storage, and secretion of bioactive neuroeffectors for cell−cell communication in health and disease.

    Read this article

    To access this article, please review the available access options below.

    Get instant access

    Purchase Access

    Read this article for 48 hours. Check out below using your ACS ID or as a guest.


    Access through Your Institution

    You may have access to this article through your institution.

    Your institution does not have access to this content. You can change your affiliated institution below.

    Supporting Information

    Jump To

    Supplementary Tables A and B. This material is available free of charge via the Internet at

    Terms & Conditions

    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system:

    Cited By

    This article is cited by 42 publications.

    1. Hongren Yao, Yuxuan Li, Yajing Zheng, Jin-Ming Lin. Stability of the Arginine–Ornithine–Citrulline Cycle Maintained by Tumor–Stroma Interactions in Cell Coculture Hydrogel Microspheres. Analytical Chemistry 2023, 95 (29) , 10999-11006.
    2. James P. Quinn, Elizabeth C. Ethier, Angelo Novielli, Aygul Malone, Christopher E. Ramirez, Lauren Salloum, Bianca A. Trombetta, Pia Kivisäkk, Michael Bremang, Stefan Selzer, Marjorie Fournier, Sudeshna Das, Yaoyi Xing, Steven E. Arnold, Becky C. Carlyle. Cerebrospinal Fluid and Brain Proteoforms of the Granin Neuropeptide Family in Alzheimer’s Disease. Journal of the American Society for Mass Spectrometry 2023, 34 (4) , 649-667.
    3. Zhenze Jiang, Christopher B. Lietz, Sonia Podvin, Michael C. Yoon, Thomas Toneff, Vivian Hook, Anthony J. O’Donoghue. Differential Neuropeptidomes of Dense Core Secretory Vesicles (DCSV) Produced at Intravesicular and Extracellular pH Conditions by Proteolytic Processing. ACS Chemical Neuroscience 2021, 12 (13) , 2385-2398.
    4. Vivian Hook, Tobias Kind, Sonia Podvin, Mine Palazoglu, Carol Tran, Thomas Toneff, Stephanie Samra, Christopher Lietz, Oliver Fiehn. Metabolomics Analyses of 14 Classical Neurotransmitters by GC-TOF with LC-MS Illustrates Secretion of 9 Cell–Cell Signaling Molecules from Sympathoadrenal Chromaffin Cells in the Presence of Lithium. ACS Chemical Neuroscience 2019, 10 (3) , 1369-1379.
    5. Christopher B. Lietz, Thomas Toneff, Charles Mosier, Sonia Podvin, Anthony J. O’Donoghue, Vivian Hook. Phosphopeptidomics Reveals Differential Phosphorylation States and Novel SxE Phosphosite Motifs of Neuropeptides in Dense Core Secretory Vesicles. Journal of the American Society for Mass Spectrometry 2018, 29 (5) , 935-947.
    6. Sifeng Mao, Jie Zhang, Haifang Li, and Jin-Ming Lin . Strategy for Signaling Molecule Detection by Using an Integrated Microfluidic Device Coupled with Mass Spectrometry to Study Cell-to-Cell Communication. Analytical Chemistry 2013, 85 (2) , 868-876.
    7. Kun Lu, Charles G. Knutson, John S. Wishnok, James G. Fox, and Steven R. Tannenbaum . Serum Metabolomics in a Helicobacter hepaticus Mouse Model of Inflammatory Bowel Disease Reveal Important Changes in the Microbiome, Serum Peptides, and Intermediary Metabolism. Journal of Proteome Research 2012, 11 (10) , 4916-4926.
    8. Mohima Mukherjee, Chandramouli Mukherjee, Vinayak Ghosh, Aamna Jain, Souren Sadhukhan, Sushma Dagar, Bhavani Shankar Sahu. Endoplasmic reticulum stress impedes regulated secretion by governing key exocytotic and granulogenic molecular switches. Journal of Cell Science 2024, 137 (6)
    9. Hratch M. Baghdassarian, Nathan E. Lewis. Resource allocation in mammalian systems. Biotechnology Advances 2024, 71 , 108305.
    10. Wei Wu, Jeroen Krijgsveld. Secretome Analysis: Reading Cellular Sign Language to Understand Intercellular Communication. Molecular & Cellular Proteomics 2024, 23 (1) , 100692.
    11. Gyunghee G Lee, Kevin Zeng, Cole M Duffy, Yadali Sriharsha, Siuk Yoo, Jae H Park, . In vivo characterization of the maturation steps of a pigment dispersing factor neuropeptide precursor in the Drosophila circadian pacemaker neurons. GENETICS 2023, 225 (1)
    12. Arlek González-Jamett, María Constanza Maldifassi, Ana María Cárdenas. Isolation and Purification of Chromaffin Granules from Adrenal Glands and Cultured Neuroendocrine Cells. 2023, 283-296.
    13. Eisuke Hayakawa, Christine Guzman, Osamu Horiguchi, Chihiro Kawano, Akira Shiraishi, Kurato Mohri, Mei-Fang Lin, Ryotaro Nakamura, Ryo Nakamura, Erina Kawai, Shinya Komoto, Kei Jokura, Kogiku Shiba, Shuji Shigenobu, Honoo Satake, Kazuo Inaba, Hiroshi Watanabe. Mass spectrometry of short peptides reveals common features of metazoan peptidergic neurons. Nature Ecology & Evolution 2022, 6 (10) , 1438-1448.
    14. Emeline Tanguy, Alexander Wolf, Qili Wang, Sylvette Chasserot-Golaz, Stéphane Ory, Stéphane Gasman, Nicolas Vitale. Phospholipase D1-generated phosphatidic acid modulates secretory granule trafficking from biogenesis to compensatory endocytosis in neuroendocrine cells. Advances in Biological Regulation 2022, 83 , 100844.
    15. Neus Barranco, Virginia Plá, Daniel Alcolea, Irene Sánchez-Domínguez, Reiner Fischer-Colbrie, Isidro Ferrer, Alberto Lleó, Fernando Aguado. Dense core vesicle markers in CSF and cortical tissues of patients with Alzheimer’s disease. Translational Neurodegeneration 2021, 10 (1)
    16. James P Quinn, Savannah E Kandigian, Bianca A Trombetta, Steven E Arnold, Becky C Carlyle. VGF as a biomarker and therapeutic target in neurodegenerative and psychiatric diseases. Brain Communications 2021, 3 (4)
    17. Gehua Wen, Hao Pang, Xu Wu, Enzhu Jiang, Xique Zhang, Xiaoni Zhan. Proteomic characterization of secretory granules in dopaminergic neurons indicates chromogranin/secretogranin-mediated protein processing impairment in Parkinson’s disease. Aging 2021, 13 (16) , 20335-20358.
    18. Ronja Göhde, Benjamin Naumann, Davis Laundon, Cordelia Imig, Kent McDonald, Benjamin H. Cooper, Frédérique Varoqueaux, Dirk Fasshauer, Pawel Burkhardt. Choanoflagellates and the ancestry of neurosecretory vesicles. Philosophical Transactions of the Royal Society B: Biological Sciences 2021, 376 (1821) , 20190759.
    19. Takumi Oti, Keita Satoh, Daisuke Uta, Junta Nagafuchi, Sayaka Tateishi, Ryota Ueda, Keiko Takanami, Larry J. Young, Antony Galione, John F. Morris, Tatsuya Sakamoto, Hirotaka Sakamoto. Oxytocin Influences Male Sexual Activity via Non-synaptic Axonal Release in the Spinal Cord. Current Biology 2021, 31 (1) , 103-114.e5.
    20. Yelda Birinci, Julia Preobraschenski, Marcelo Ganzella, Reinhard Jahn, Yongsoo Park. Isolation of large dense-core vesicles from bovine adrenal medulla for functional studies. Scientific Reports 2020, 10 (1)
    21. Elles Konijnenberg, Betty M. Tijms, Johan Gobom, Valerija Dobricic, Isabelle Bos, Stephanie Vos, Magda Tsolaki, Frans Verhey, Julius Popp, Pablo Martinez-Lage, Rik Vandenberghe, Alberto Lleó, Lutz Frölich, Simon Lovestone, Johannes Streffer, Lars Bertram, Kaj Blennow, Charlotte E. Teunissen, Robert Veerhuis, August B. Smit, Philip Scheltens, Henrik Zetterberg, Pieter Jelle Visser. APOE ε4 genotype-dependent cerebrospinal fluid proteomic signatures in Alzheimer’s disease. Alzheimer's Research & Therapy 2020, 12 (1)
    22. Mary Beth Bauer, Kevin P.M. Currie. Adrenal Medulla Hormones. 2020, 635-653.
    23. Deepti Dabral, Jens R Coorssen. Combined targeted Omic and Functional Assays Identify Phospholipases A2 that Regulate Docking/Priming in Calcium-Triggered Exocytosis. Cells 2019, 8 (4) , 303.
    24. Jennifer A. Ross, Beverly A.S. Reyes, Elisabeth J. Van Bockstaele. Amyloid beta peptides, locus coeruleus-norepinephrine system and dense core vesicles. Brain Research 2019, 1702 , 46-53.
    25. Prabhodh S. Abbineni, Jens R. Coorssen. Sphingolipids modulate docking, Ca2+ sensitivity and membrane fusion of native cortical vesicles. The International Journal of Biochemistry & Cell Biology 2018, 104 , 43-54.
    26. Meyer B. Jackson. Chemistry in a vesicle. Journal of General Physiology 2017, 149 (10) , 893-896.
    27. Bhavani S. Sahu, Paul T. Manna, James R. Edgar, Robin Antrobus, Sushil K. Mahata, Alessandro Bartolomucci, Georg H. H. Borner, Margaret S. Robinson, . Role of clathrin in dense core vesicle biogenesis. Molecular Biology of the Cell 2017, 28 (20) , 2676-2685.
    28. Agata Witkowska, Reinhard Jahn. Rapid SNARE-Mediated Fusion of Liposomes and Chromaffin Granules with Giant Unilamellar Vesicles. Biophysical Journal 2017, 113 (6) , 1251-1259.
    29. Thomas F.J. Martin. Control of Hormone Secretion. 2016, 30-40.e5.
    30. Sonia Podvin, Richard Bundey, Thomas Toneff, Michael Ziegler, Vivian Hook. Profiles of secreted neuropeptides and catecholamines illustrate similarities and differences in response to stimulation by distinct secretagogues. Molecular and Cellular Neuroscience 2015, 68 , 177-185.
    31. Jakob Albrethsen, Jens P Goetze, Anders H Johnsen. Mining the granule proteome: a potential source of endocrine biomarkers. Biomarkers in Medicine 2015, 9 (3) , 259-265.
    32. Kuixing Zhang, Nilima Biswas, Jiaur R. Gayen, Jose Pablo Miramontes‐Gonzalez, C. Makena Hightower, Maja Mustapic, Manjula Mahata, Chun‐Teng Huang, Vivian Y. Hook, Sushil K. Mahata, Sucheta Vaingankar, Daniel T. O'Connor. Chromogranin B: intra‐ and extra‐cellular mechanisms to regulate catecholamine storage and release, in catecholaminergic cells and organisms. Journal of Neurochemistry 2014, 129 (1) , 48-59.
    33. Holger Cynis, Lydiane Funkelstein, Thomas Toneff, Charles Mosier, Michael Ziegler, Birgit Koch, Hans-Ulrich Demuth, Vivian Hook. Pyroglutamate-Amyloid-β and Glutaminyl Cyclase Are Colocalized with Amyloid-β in Secretory Vesicles and Undergo Activity-Dependent, Regulated Secretion. Neurodegenerative Diseases 2014, 14 (2) , 85-97.
    34. Thomas Toneff, Lydiane Funkelstein, Charles Mosier, Armen Abagyan, Michael Ziegler, Vivian Hook. Beta-amyloid peptides undergo regulated co-secretion with neuropeptide and catecholamine neurotransmitters. Peptides 2013, 46 , 126-135.
    35. George E. Craft, Anshu Chen, Angus C. Nairn. Recent advances in quantitative neuroproteomics. Methods 2013, 61 (3) , 186-218.
    36. Shane Minogue, Mark G. Waugh. Lipid rafts, microdomain heterogeneity and inter‐organelle contacts: Impacts on membrane preparation for proteomic studies. Biology of the Cell 2012, 104 (10) , 618-627.
    37. Salah Elias, Charlène Delestre, Stéphane Ory, Sébastien Marais, Maïté Courel, Rafael Vazquez-Martinez, Sophie Bernard, Laurent Coquet, Maria M. Malagon, Azeddine Driouich, Philippe Chan, Stéphane Gasman, Youssef Anouar, Maité Montero-Hadjadje. Chromogranin A Induces the Biogenesis of Granules with Calcium- and Actin-Dependent Dynamics and Exocytosis in Constitutively Secreting Cells. Endocrinology 2012, 153 (9) , 4444-4456.
    38. Weiya Douglas Lu, Lydiane Funkelstein, Thomas Toneff, Thomas Reinheckel, Christoph Peters, Vivian Hook. Cathepsin H functions as an aminopeptidase in secretory vesicles for production of enkephalin and galanin peptide neurotransmitters. Journal of Neurochemistry 2012, 122 (3) , 512-522.
    39. Lydiane Funkelstein, W. Douglas Lu, Britta Koch, Charles Mosier, Thomas Toneff, Laurent Taupenot, Daniel T. O'Connor, Thomas Reinheckel, Christoph Peters, Vivian Hook. Human Cathepsin V Protease Participates in Production of Enkephalin and NPY Neuropeptide Neurotransmitters. Journal of Biological Chemistry 2012, 287 (19) , 15232-15241.
    40. Javier Álvarez. Calcium dynamics in the secretory granules of neuroendocrine cells. Cell Calcium 2012, 51 (3-4) , 331-337.
    41. Vivian Hook, Lydiane Funkelstein, Jill Wegrzyn, Steven Bark, Mark Kindy, Gregory Hook. Cysteine Cathepsins in the secretory vesicle produce active peptides: Cathepsin L generates peptide neurotransmitters and cathepsin B produces beta-amyloid of Alzheimer's disease. Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics 2012, 1824 (1) , 89-104.
    42. Vivian Hook, Steven Bark, Nitin Gupta, Mark Lortie, Weiya D. Lu, Nuno Bandeira, Lydiane Funkelstein, Jill Wegrzyn, Daniel T. O’Connor, Pavel Pevzner. Neuropeptidomic Components Generated by Proteomic Functions in Secretory Vesicles for Cell–Cell Communication. The AAPS Journal 2010, 12 (4) , 635-645.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    You’ve supercharged your research process with ACS and Mendeley!

    STEP 1:
    Click to create an ACS ID

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Your Mendeley pairing has expired. Please reconnect