Prodynorphin transcripts and proteins differentially expressed and regulated in the adult human brain

Section of Psychiatry, Department of Clinical Neuroscience, Karolinska Hospital, Stockholm, Sweden.
The FASEB Journal (Impact Factor: 5.04). 10/2005; 19(11):1543-5. DOI: 10.1096/fj.05-3743fje
Source: PubMed


Transcription from multiple promoters along with alternative mRNA splicing constitutes the basis for cell-specific gene expression and mRNA and protein diversity. The prodynorphin gene (PDYN) gives rise to prodynorphin (PDYN), precursor to dynorphin opioid peptides that regulate diverse physiological functions and are implicated in various neuropsychiatric disorders. Here, we characterized PDYN transcripts and proteins in the adult human brain and studied PDYN processing and intracellular localization in model cell lines. Seven PDYN mRNAs were identified in the human brain; two of the transcripts, FL1 and FL2, encode the full-length PDYN. The dominant, FL1 transcript shows high expression in limbic-related structures such as the nucleus accumbens and amygdala. The second, FL2 transcript is only expressed in few brain structures such as the claustrum and hypothalamus. FL-PDYN was identified for the first time in the brain as the dominant PDYN protein product. Three novel PDYNs expressed from spliced or truncated PDYN transcripts either lack a central segment but are still processed into dynorphins, or are translated into N-terminally truncated proteins. One truncated PDYN is located in the cell nucleus, suggesting a novel nonopioid function for this protein. The complexity of PDYN expression and diversity of its protein products may be relevant for diverse levels of plasticity in adaptive responses for the dynorphin system.

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    • "Dynorphin peptides reduce basal and drug-induced dopamine levels in different areas of the dopaminergic, nigrostriatal, and mesolimbic, mesocortical systems. Expression of Pdyn is increased by cocaine behavior in anxiety tests demonstrating the anxiogenic role of prodynorphin-derived peptides [Wittmann et al., 2009] Pdyn contains four exons: exon 1 and 2 encode the 5 0 UTR, exon 3 encodes a signal peptide, and exon 4 encodes the dynorphin peptides and has multiple transcription start sites located in exons 1 and 4 and introns 1 and 2 [Nikoshkov et al., 2005; Tejeda et al., 2012]. It has been identified some alternatively spliced Pdyn transcripts, which contribute to dynorphin/ Oprk1 system diversity [Kimura et al., 2006]. "
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    • "This SNP has been described as a tag SNP for a haplotype block within the PDYN gene (across exons and introns 1 and 2) [20]. Yet, it is located in an area that may be involved in the regulation of transcription initiation from multiple sites, giving rise to one of the PDYN transcripts [31]. Moreover, the low risk rs2281285 major allele resides within the sequence that allows DNA-binding for several transcription factors, whereas the high risk rs2281285 minor allele destroys this sequence [21]. "
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    • "The transcription start sites used by the PDYN promoter construct were similar to those used by the PDYN gene in human cells and tissues (Telkov et al. 1998; Nikoshkov et al. 2005), and correct splicing of the construct occurred in the three different cell lines. We also showed that alternative transcription start sites located in intron 1, upstream of exon 2, were utilized under specific conditions and were cell specific. "
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