Disease relevance of PDYN

• Increased striatal pre-proenkephalin B expression is associated with dyskinesia in Parkinson's disease [1].
• Normal epithelial cells of human endometrium, and Ishikawa human endometrial adenocarcinoma cells (an in vitro model for the study of steroid hormone effects on human endometrium) have been found to express and secrete opioid peptides deriving from proenkephalin, prodynorphin, and proopiomelanocortin [2].
• On the other hand, prodynorphin (another endogenous opioid precursor) is not present in normal adrenal chromaffin cells, but it is synthesized by human pheochromocytomas [3].
• Unilateral inflammation in the hindpaw of the rat results in an increase in the expression of preprodynorphin and preproenkephalin mRNA in the spinal cord, which parallels the behavioral hyperalgesia associated with the inflammation [4].
• Here, we show that a direct protein-protein interaction between DREAM and the CREM repressor isoform, alphaCREM, prevents binding of DREAM to the DRE and suggests a mechanism for cyclic AMP-dependent derepression of the prodynorphin gene in human neuroblastoma cells [5].

Psychiatry related information on PDYN

• Subjects with major depression or bipolar disorder show reduction of prodynorphin mRNA expression in discrete nuclei of the amygdaloid complex [6].
• These findings indicate specific prodynorphin amygdala impairment in association with mood disorder [6].
• Dynorphin was found to be involved in many pathophysiological processes so that the described prodynorphin alleles may correlate with the occurrence of several diseases, for example, drug addiction [7].
• Opioid peptides in Huntington's disease: alterations in prodynorphin and proenkephalin system [8].
• Whereas down-regulation of preproenkephalin and preprodynorphin genes was evident in all heroin users, the effects were exaggerated in 118G subjects and were most prominent for preproenkephalin in the nucleus accumbens shell [9].

High impact information on PDYN

• The transcriptional repressor DREAM acts constitutively to suppress prodynorphin expression in spinal cord neurons [10].
• In the granule cells of the hippocampus, glutamate coexists with opioid peptides derived from the proenkephalin and prodynorphin genes [11].
• Furthermore, in rats depleted of serotonin by intrathecal administration of 5,7-dihydroxytryptamine, the induction of prodynorphin after noxious stimulation is dramatically decreased compared with the induction in sham-operated rats [12].
• Addition of the specific 1A agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) to the culture, at concentrations similar to that needed for transactivation of the prodynorphin gene, also significantly increases cAMP levels [12].
• Hybridization of probes to Southern blots made with DNAs from a rodent-human somatic-cell hybrid panel indicates localization of proenkephalin to human chromosome 8 and of prodynorphin to human chromosome 20 [13].

Chemical compound and disease context of PDYN

• Effect of antisense FosB and CREB on the expression of prodynorphin gene in rats with levodopa-induced dyskinesias [14].

Biological context of PDYN

• We performed a case control association study in 155 patients with nonlesional temporal lobe epilepsy and 202 controls and found that PDYN promotor low-expression L-alleles confer an increased risk for temporal lobe epilepsy in patients with a family history for seizures [15].
• The combined ARVP/PT/PDYN group was also found to demonstrate linkage with other anonymous DNA segments on chromosome 20, including D20S4, D20S5, and D20S6 [16].
• These linkage relationships establish that the secretory and transcriptional associations of ARVP and PDYN extend to a close physical relationship in the human genome [16].
• Pre-PDYN gene expression also is found in neurons of the dorsomedial nucleus, ventromedial nucleus, caudal magnocellular portion of the paraventricular nucleus, dorsolateral supraoptic nucleus, tuberomammillary nucleus, caudal lateral hypothalamus, and retrochiasmatic area [17].
• The obtained data indicate that up-regulation of the PDYN gene expression in the caudate/putamen results from direct pharmacological actions of cocaine rather than from the motivational and cognitive processes underlying active self-administration of the drug [18].

Anatomical context of PDYN

• Pre-PDYN message is especially abundant in neurons of the tuberal and mammillary regions, with a distinct population of labeled cells in the premammillary nucleus and dorsal posterior hypothalamus [17].
• In situ hybridization analysis revealed that levels of the PDYN mRNA were significantly increased in the caudate/putamen, to the same extent in rats self-administering cocaine as in animals receiving noncontingent injections of the drug at the same frequency and dosage [18].
• No changes in the expression of the PDYN gene were detected in the nucleus accumbens or in the central nucleus of amygdala [18].
• In the present study, effects of response-dependent (contingent) and response-independent (noncontingent) cocaine administration on the PENK and PDYN gene expression in the rat forebrain have been directly compared using the "yoked" self-administration procedure [18].
• In contrast to neurons that express pre-POMC, neurons expressing pre-PDYN and pre-PENK are more widely represented throughout the hypothalamus and extrahypothalamic structures [17].

Associations of PDYN with chemical compounds

• However, we observed a significant interactive effect with the receptor 3 of dopamine gene (DRD3); in particular, the frequency of subjects carrying PDYN allele 3 being also homozygotes for DRD3 Gly allele (of Ser9Gly polymorphism) was significantly greater in patients than controls [19].
• We conclude that PDYN gene polymorphism alone does not alter the risk for schizophrenia but, by an epistatic interaction with the Gly allele of DRD3 gene, may contribute to the susceptibility to this disorder [19].
• Linkage relationships of human arginine vasopressin-neurophysin-II and oxytocin-neurophysin-I to prodynorphin and other loci on chromosome 20 [16].
• Proenkephalin B-derived opioid peptides, such as dynorphin1-17, dynorphin1-8, dynorphin B, alpha-neo-endorphin and beta-neo-endorphin in the human hypothalamo-neurohypophyseal tract were quantitated and characterized by the combined use of various radioimmunoassays, gel filtration, high performance liquid chromatography and enzymatic cleavage [20].
• Most interestingly, activation of U-937 cells with lipopolysaccharide (LPS) led to a decrease in PDYN mRNA levels [21].

Regulatory relationships of PDYN

• In comparison to stimulated control hamsters, a significantly lower prodynorphin expression was found in several limbic areas of stimulated mutant hamsters during the manifestation of dystonia, while preproenkephalin mRNA was significantly lower in the anterior and dorsal striatal subregions and in nucleus accumbens [22].

Other interactions of PDYN

• However, pre-PDYN and pre-PENK cells differ from one another in distribution [17].
• Northern blot hybridization of RNA from these cells showed the presence of a 1.2-kb POMC and a 2.4-kb PDYN transcript [23].
• Polymerase chain reaction amplification of the PDYN promoter was performed and various genotypes were determined on the basis of differing sizes of the polymerase chain reaction products [24].
• Family-based analyses demonstrated associations between alcohol dependence and multiple SNPs in the promoter and 3' end of PDYN, and in intron 2 of OPRK1 [25].
• Prodynorphin gene expression relates to NF-kappa B factors [26].

Analytical, diagnostic and therapeutic context of PDYN

• We designed primers for polymerase chain reaction (PCR) to amplify sequences of the promoter region of the prodynorphin gene containing the repeat element [27].
• PDYN mRNA was expressed at a detectable level, measured with a standard RT-PCR method in U-937 cells, but not in Jurkat and Raji cells, which are human T and B lymphocytes, respectively [21].
• Electron microscopy showed coexistence of PDYN and dynorphins in the same axon terminals with occasional codistribution in individual dense core vesicles [28].
• To determine whether human hypothalamic prodynorphin is also under osmotic regulation, we measured plasma IR-dynorphin, plasma IR-AVP, and serum sodium immediately before and during the infusion of normal or hypertonic saline in normal human volunteers [29].
• Radioimmunochemistry (RIA) and immunocytochemistry (ICC) were used to measure proenkephalin and prodynorphin peptides in the brain of a genetic model of epilepsy, the seizure-sensitive (SS) Mongolian gerbil [30].

References