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

ABSTRACT 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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Available from: Gvido Cebers, Sep 28, 2015
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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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    ABSTRACT: One of the proposed psychobiological pathways of craving attributes the desire for drinking in the context of tension, discomfort or unpleasant emotions, to "negative" (or "relief") craving. The aim of this study was to replicate a previously reported association of the PDYN rs2281285 variant with negative craving using a different phenotyping approach. The TaqMan® Genotyping Assay was used to genotype the rs2281285 variant in 417 German alcohol-dependent subjects. The presence of negative/relief craving was assessed by asking if participants ever ingested alcohol to avoid unwanted emotional or somatic discomfort. The minor allele of rs2281285 was associated with an increased risk of drinking to avoid/escape unwanted emotional or somatic events (OR = 2.29, 95% CI = 1.08-4.85, p = 0.0298). Despite the use of a different phenotyping approach to the measurement of negative craving, our results confirm the association between negative craving and PDYN rs2281285. Genetic markers of negative craving may help to identify subgroups of alcohol-dependent individuals vulnerable to relapse in the context of negative emotions or somatic discomfort, leading to the development of specifically tailored treatment strategies.
    PLoS ONE 11/2013; 8(11):e78688. DOI:10.1371/journal.pone.0078688 · 3.23 Impact Factor
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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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    ABSTRACT: A polymorphic 68-bp tandem repeat has been identified within the promoter of the human prodynorphin (PDYN) gene. We found that this 68-bp repeat in the PDYN promoter occurs naturally up to five times. We studied the effect of the number of 68-bp repeats, and of a SNP (rs61761346) found within the repeat on PDYN gene promoter activity. Thirteen promoter forms, different naturally occurring combinations of repeats and the internal SNP, were cloned upstream of the luciferase reporter gene, transfected into human SK-N-SH, H69, or HEK293 cells. Cells were then stimulated with TPA or caffeine. We found cell-specific effects of the number of 68-bp repeats on the transcriptional activity of the PDYN promoter. In SK-N-SH and H69 cells, three or four repeats led to lower expression of luciferase than did one or two repeats. The opposite effect was found in HEK293 cells. The SNP also had an effect on PDYN gene expression in both SK-N-SH and H69 cells; promoter forms with the A allele had significantly higher expression than promoter forms with the G allele. These results further our understanding of the complex transcriptional regulation of the PDYN gene promoter.
    Addiction Biology 04/2011; 16(2):334-46. DOI:10.1111/j.1369-1600.2010.00248.x · 5.36 Impact Factor
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