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Opioid precursor protein isoform is targeted to the cell nuclei in the human brain
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
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2017 (English)In: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1861, no 2, 246-255 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Neuropeptide precursors are traditionally viewed as proteins giving rise to small neuropeptide molecules. Prodynorphin (PDYN) is the precursor protein to dynorphins, endogenous ligands for the κ-opioid receptor. Alternative mRNA splicing of neuropeptide genes may regulate cell- and tissue-specific neuropeptide expression and produce novel protein isoforms. We here searched for novel PDYN mRNA and their protein product in the human brain.

METHODS: Novel PDYN transcripts were identified using nested PCR amplification of oligo(dT) selected full-length capped mRNA. Gene expression was analyzed by qRT-PCR, PDYN protein by western blotting and confocal imaging, dynorphin peptides by radioimmunoassay. Neuronal nuclei were isolated using fluorescence-activated nuclei sorting (FANS) from postmortem human striatal tissue. Immunofluorescence staining and confocal microscopy was performed for human caudate nucleus.

RESULTS: Two novel human PDYN mRNA splicing variants were identified. Expression of one of them was confined to the striatum where its levels constituted up to 30% of total PDYN mRNA. This transcript may be translated into ∆SP-PDYN protein lacking 13 N-terminal amino acids, a fragment of signal peptide (SP). ∆SP-PDYN was not processed to mature dynorphins and surprisingly, was targeted to the cell nuclei in a model cellular system. The endogenous PDYN protein was identified in the cell nuclei in human striatum by western blotting of isolated neuronal nuclei, and by confocal imaging.

CONCLUSIONS AND GENERAL SIGNIFICANCE: High levels of alternatively spliced ∆SP-PDYN mRNA and nuclear localization of PDYN protein suggests a nuclear function for this isoform of the opioid peptide precursor in human striatum.

Place, publisher, year, edition, pages
2017. Vol. 1861, no 2, 246-255 p.
Keyword [en]
Alternative splicing, Human brain, Neuropeptide precursor protein, Nuclear localization, Prodynorphin
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-316836DOI: 10.1016/j.bbagen.2016.11.002ISI: 000392680200023PubMedID: 27838394OAI: oai:DiVA.org:uu-316836DiVA: diva2:1079131
Funder
Swedish Research Council, K2014-62X-12190-19-5Swedish Research Council Formas, 2009-1709 259-2012-23
Note

Shared first authorship for Kononenko O., Bazov I.

Available from: 2017-03-07 Created: 2017-03-07 Last updated: 2017-03-23

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Kononenko, OlgaBazov, IgorWatanabe, HiroyukiDyachok, OlegAndersson, MalinYakovleva, TatianaBakalkin, Georgy
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Department of Pharmaceutical BiosciencesDepartment of Medical Cell Biology
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Biochimica et Biophysica Acta
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