Mechanism of Sorting Proopiomelanocortin and Proenkephalin to the Regulated Secretory Pathway of Neuroendocrine Cells

Authors

  • Y. PENG LOH,

    Corresponding author
    1. Section on Cellular Neurobiology, Laboratory of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA
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  • ALEX MALDONADO,

    1. Section on Cellular Neurobiology, Laboratory of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA
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  • CHUNFA ZHANG,

    1. Section on Cellular Neurobiology, Laboratory of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA
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  • WINNIE H. TAM,

    1. Section on Cellular Neurobiology, Laboratory of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA
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  • NIAMH CAWLEY

    1. Section on Cellular Neurobiology, Laboratory of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA
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Address for correspondence: Y. Peng Loh, Section on Cellular Neurobiology, Laboratory of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, 49 Convent Dr., Rm. 5A38, Bethesda, MD 20892. Voice: 301-496-3239; fax: 301-496-9938; ypl@codon.nih.gov.

Abstract

Abstract: Proopiomelanocortin (POMC) and proenkephalin (PE) are synthesized at the endoplasmic reticulum and transported to the trans-Golgi network (TGN) where they are sorted and packaged into dense-core granules of the regulated secretory pathway (RSP). The mechanism of sorting POMC and PE to the RSP in neuroendocrine cells was investigated. Consensus sorting signals comprising two acidic residues and two hydrophobic residues exposed on the surface of N-POMC1-26 and N-PE1-32 were identified and shown to be sufficient and necessary for targeting POMC and PE to the RSP in PC12, Neuro2a, and AtT-20 cells. The acidic residues of these sorting signals bind specifically to basic residues on the sorting receptor membrane, carboxypeptidase E (CPE), to effect sorting to the RSP. Analysis of POMC and PE sorting in Neuro2a cells depleted of CPE by CPE antisense RNA, and Cpefat/fat mouse pituitary cells lacking CPE showed missorting of both these molecules to the constitutive pathway in vivo. Thus, POMC and PE are sorted to the RSP at the TGN by a mechanism involving the interaction of a specific sorting signal on these molecules with the sorting receptor, CPE.

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