Endogenous Opioid Peptides and Alternatively Spliced Mu Opioid Receptor Seven Transmembrane Carboxyl-Terminal Variants

Abrimian, Anna; Kraft, Tamar T.; Pan, Ying‐Xian

doi:10.3390/ijms22073779

Cited by 16 publications

(16 citation statements)

References 108 publications

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“…From the biochemical point of view, the two PENK-derived peptides include the amino acidic residues 142-157 and 236-251. Given that the protein precursor PENK contains several cleavage sites between the amino acid residues 157 and 236 [17], the measured peptides in the CSF belong to distinct cleavage products with possibly different pathophysiological destinies.…”

Section: Discussionmentioning

confidence: 99%

Prodynorphin and Proenkephalin in Cerebrospinal Fluid of Sporadic Creutzfeldt–Jakob Disease

Abu‐Rumeileh

Barschke

Oeckl

et al. 2022

IJMS

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Proenkephalin (PENK) and prodynorphin (PDYN) are endogenous opioid peptides mainly produced in the striatum and, to a lesser extent, in the cerebral cortex. Dysregulated metabolism and altered cerebrospinal fluid (CSF) levels of PENK and PDYN have been described in several neurodegenerative diseases. However, no study to date investigated these peptides in the CSF of sporadic Creutzfeldt–Jakob disease (sCJD). Using liquid chromatography-multiple reaction monitoring mass spectrometry, we evaluated the CSF PDYN- and PENK-derived peptide levels in 25 controls and 63 patients with sCJD belonging to the most prevalent molecular subtypes (MM(V)1, VV2 and MV2K). One of the PENK-derived peptides was significantly decreased in each sCJD subtype compared to the controls without a difference among subtypes. Conversely, PDYN-derived peptides were selectively decreased in the CSF of sCJD MV2K, a subtype with a more widespread overall pathology compared to the sCJD MM(V)1 and the VV2 subtypes, which we confirmed by semiquantitative analysis of cortical and striatal neuronal loss and astrocytosis. In sCJD CSF PENK and PDYN were associated with CSF biomarkers of neurodegeneration but not with clinical variables and showed a poor diagnostic performance. CSF PDYN and PENK-derived peptides had no significant diagnostic and prognostic values in sCJD; however, the distinct marker levels between molecular subtypes might help to better understand the basis of phenotypic heterogeneity determined by divergent neuronal targeting.

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Section: Discussionmentioning

confidence: 99%

Prodynorphin and Proenkephalin in Cerebrospinal Fluid of Sporadic Creutzfeldt–Jakob Disease

Abu‐Rumeileh

Barschke

Oeckl

et al. 2022

IJMS

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“…All the 7TM C-terminal variants display similar binding affinities towards mu opioids since they share the same binding pocket. However, several endogenous opioid peptides such as β-endorphin and dynorphin A show small but significant differences in the K i values among some 7TM C-terminal variants [ 49 , 50 , 51 , 52 , 53 , 54 , 55 ], raising an interesting question of how different C-terminal sequences influence the shared binding pocket. Although the crystal structure of MOR-1 has been revolved [ 56 , 57 ], the N- and C-terminal sequences of the constructs were truncated in order to stabilize the crystal structure.…”

Section: Alternative Pre-mrna Splicing Of the Mu Opioid Receptor Gene...mentioning

confidence: 99%

Exploring Pharmacological Functions of Alternatively Spliced Variants of the Mu Opioid Receptor Gene, Oprm1, via Gene-Targeted Animal Models

Kang

Liu

et al. 2022

IJMS

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The mu opioid receptor has a distinct place in the opioid receptor family, since it mediates the actions of most opioids used clinically (e.g., morphine and fentanyl), as well as drugs of abuse (e.g., heroin). The single-copy mu opioid receptor gene, OPRM1, goes through extensive alternative pre-mRNA splicing to generate numerous splice variants that are conserved from rodents to humans. These OPRM1 splice variants can be classified into three structurally distinct types: (1) full-length 7 transmembrane (TM) carboxyl (C)-terminal variants; (2) truncated 6TM variants; and (3) single TM variants. Distinct pharmacological functions of these splice variants have been demonstrated by both in vitro and in vivo studies, particularly by using several unique gene-targeted mouse models. These studies provide new insights into our understanding of the complex actions of mu opioids with regard to OPRM1 alternative splicing. This review provides an overview of the studies that used these gene-targeted mouse models for exploring the functional importance of OPRM1 splice variants.

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“…That this level of atypia may parallel the evolutionary importance of OPRM1 gene-splicing is strengthened by the preservation of alternative splicing events observed in rodents and humans. 16 Distinguished by the number of transmembrane domains, at least 30 splice variants have been identified; the variants are aggregated into three groups based on their OPRM1 isoform. The first group, generated by 3’ splicing, expresses the traditional seven transmembrane domains with variability in the C-terminus region.…”

Section: A Descriptive Primermentioning

confidence: 99%

Spoken and Unspoken Matters Regarding the Use of Opioids in Cancer

Rogers¹,

Higa²

2022

JPR

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Pain is among the most debilitating symptoms in patients with cancer. Except for their relatively frequent use during end-of-life care, opioids are often, though not routinely, prescribed during the course of the disease. Whereas the clinical phenomena of tolerance, dependence, and addiction are invariably recognized, the molecular mechanisms which effect these outcomes are not fully understood, even among health care professionals. Also uncertain is the possible unfavorable effect of these agents on cancer progression and survival, an association that may be related to the expression of opioid receptors in some tumors. An intriguing corollary of the latter finding is that cancer cells may also manifest equivalents of the three maladaptive phenomena. Accordingly, instead of re-addressing the societal and epidemiological impact of opioids, this paper has three alternative foci. The first, and most subordinate, focuses on the mu opioid receptor; the second, centers on the unresolved question regarding the potential adverse effect of opioids on tumor growth; the third, and most compelling, concentrates on the cellular apparatus and influences that modulate tolerance, dependence, and addiction in certain cancers exposed to opioids.

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Endogenous Opioid Peptides and Alternatively Spliced Mu Opioid Receptor Seven Transmembrane Carboxyl-Terminal Variants

Cited by 16 publications

References 108 publications

Prodynorphin and Proenkephalin in Cerebrospinal Fluid of Sporadic Creutzfeldt–Jakob Disease

Prodynorphin and Proenkephalin in Cerebrospinal Fluid of Sporadic Creutzfeldt–Jakob Disease

Exploring Pharmacological Functions of Alternatively Spliced Variants of the Mu Opioid Receptor Gene, Oprm1, via Gene-Targeted Animal Models

Spoken and Unspoken Matters Regarding the Use of Opioids in Cancer

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