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Neurosecretory Protein Trafficking and Dense-Core Granule Biogenesis in Neuroendocrine Cells

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Handbook of Neurochemistry and Molecular Neurobiology

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Abstract:

Neuropeptides and brain-derived neurotrophic factor (BDNF) are secreted from neurons in an activity-dependent manner through the regulated secretory pathway (RSP). Neuropeptides and BDNF, initially synthesized as a proform, are sorted at the trans-Golgi network (TGN) along with their processing enzymes, prohormone convertases (PC) 1/3 and 2 and carboxypeptidase E (CPE), into the dense-core secretory granules (DCGs) for secretion. Consensus RSP sorting signals have been identified in proopiomelanocortin (POMC), insulin, and BDNF, which are sufficient and necessary for targeting these proteins to secretory granules. These signals are conformation-dependent and consist of a pair of acidic amino acids ∼10–15 Å apart and an aliphatic hydrophobic amino acid ∼5–6 Å away from each of the acidic residues. The acidic residues in the motif interact with a sorting receptor, membrane CPE, at the TGN to effect sorting into granules. CPE-deficient mouse models verify the functioning of the CPE-mediated sorting mechanism in vivo. Other less well studied putative proneuropeptide sorting motifs and mechanisms are also discussed. The processing enzymes, however, are sorted to the DCGs by insertion of their C-terminal domain into cholesterol–sphingolipid-rich membrane microdomains (lipid rafts), which are the proposed sites of budding to form the DCGs at the TGN. In addition to sorting of cargo to the DCGs, molecules driving the budding of the DCGs from the TGN and regulating granule quantity are important components for regulated secretion of neuropeptides. The granins, major proteins in DCGs, as well as proneuropeptides form aggregates that appear to be able to provide the necessary driving force to form DCGs. In addition, cholesterol plays a critical role in the pinching off of the granules at the TGN, as evidenced from cholesterol depletion studies in an endocrine cell line and in cholesterol-deficient mouse models. Finally, studies have identified chromogranin A (CgA) as a regulator of quantitative DCG biogenesis in neuroendocrine cells. CgA acts by regulating the stability of secretory granule proteins in the Golgi apparatus, thereby controlling the number of DCGs that can be formed.

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Abbreviations

BDNF:

brain-derived neurotrophic factor

RSP:

regulated secretary pathway

TGN:

trans-Golgi network

PC:

prohormone convertases

CPE:

carboxypeptidase E

DCGs:

dense-core secretory granules

POMC:

proopiomelanocortin

CgA:

chromogranin A

ISGs:

immature secretory granules

NMR:

nuclear magnetic resonance

NGF:

nerve growth factor

SLOS:

Smith–Lemli–Opitz syndrome

Sc5d:

lathosterol desaturase

GUVs:

giant unilamellar vesicles

CgB:

chromogranin B

SecII:

secretogranin II

PTB:

Polypyrimidine-tract binding protein

ICA512/IA2:

receptor-tyrosine-phosphatase-like protein

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Authors
  1. T. Kim
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  2. M. Gondré-Lewis
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  3. I. Arnaoutova
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  4. N. Cawley
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  5. Y. Peng Loh
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Editor information

Editors and Affiliations

  1. Center for Neurochemistry, Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, Orangeburg, Newyork, 10962, USA

    Abel Lajtha (Director) (Director)

  2. Department of Neurosciences Division of Neurology, Medical University of South Carolina, 96 Jonathan Lucas Street Suite 309, Charleston, SC 29425, USA

    Naren Banik (Professor) (Professor)

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Kim, T., Gondré-Lewis, M., Arnaoutova, I., Cawley, N., Peng Loh, Y. (2007). Neurosecretory Protein Trafficking and Dense-Core Granule Biogenesis in Neuroendocrine Cells. In: Lajtha, A., Banik, N. (eds) Handbook of Neurochemistry and Molecular Neurobiology. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-30379-6_3

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