Alternative Pre‐mRNA Splicing of Mu Opioid Receptor Gene

Pan, Ying Xian

doi:10.1002/9781118398890.ch6

Cited by 3 publications

(9 citation statements)

References 99 publications

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“…Specifically, we identified 16 potential 6TM transcript variants in OPRM1 , three in OPRD1 and OPRK1 , and four in OPRL1 . Since some of these splice variants show different ligand binding or signaling pathways and the highest level of SNP density in human OPRM1 gene locus (Stevens 2009 ; Pan 2014 ), the enrichment of alternative events in human OPRM1 gene locus may support the hypothesis that OPRM1 differs from the other OPRs by higher measurable evolutionary pressure and presence of signature of adaptive evolution in the gene locus.…”

Section: Discussionmentioning

confidence: 98%

Alternative Splicing of Opioid Receptor Genes Shows a Conserved Pattern for 6TM Receptor Variants

et al. 2020

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The opioid receptor (OPR) family comprises the mu-, delta-, and kappa-opioid, and nociceptin receptors that belong to the superfamily of 7-transmembrane spanning G protein-coupled receptors (GPCRs). The mu-opioid receptor is the main target for clinically used opioid analgesics, and its biology has been extensively studied. The N-terminally truncated 6TM receptors isoform produced through alternative splicing of the OPRM1 gene displays unique signaling and analgesic properties, but it is unclear if other OPRs have the same ability. In this study, we have built a comprehensive map of alternative splicing events that produce 6TM receptor variants in all the OPRs and demonstrated their evolutionary conservation. We then obtained evidence for their translation through ribosomal footprint analysis. We discovered that N-terminally truncated 6TM GPCRs are rare in the human genome and OPRs are overrepresented in this group. Finally, we also observed a significant enrichment of 6TM GPCR genes among genes associated with pain, psychiatric disorders, and addiction. Understanding the biology of 6TM receptors and leveraging this knowledge for drug development should pave the way for novel therapies.

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Section: Discussionmentioning

confidence: 98%

Alternative Splicing of Opioid Receptor Genes Shows a Conserved Pattern for 6TM Receptor Variants

et al. 2020

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“…These findings augment human studies to develop novel µ opioid receptors ligands having therapeutic potential while avoiding tolerance 74. Multiple receptors subtypes (isoforms) play a critical role in an individual’s response to maintenance pharmacotherapies that warrant the need to consider each subtype of µ opioid receptor splice variants while developing novel and effective personalized medications for addiction 70,75,76…”

Section: Medication Strategies For Opioid Addictionmentioning

confidence: 88%

“…Alternative splicing is an efficient process that results in multiple subtypes of a wild type protein with differential and diverse functional spectrum. Alternative splicing in µ opioid receptors is responsible for the generation of multiple subtypes of µ opioid receptors with heterogeneous and diverse functions 70. Studies have shown that subtypes of µ opioid receptors may differ from each other in the term of their amino acid and axons patterns and functional spectrum 71,72.…”

Section: Medication Strategies For Opioid Addictionmentioning

confidence: 99%

<p><em>OPRM1</em> A118G Polymorphisms and Its Role in Opioid Addiction: Implication on Severity and Treatment Approaches</p>

Taqi¹,

Faisal²,

Zaman³

2019

PGPM

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The epidemic of opioid addiction is shaping up as the most serious clinical issues of current times. Opioids have the greatest propensity to develop addiction after first exposure. Molecular, genetic variations, epigenetic alterations, and environmental factors are also implicated in the development of opioid addiction. Genetic and epigenetic variations in candidate genes have been identified for their associations with opioid addiction. OPRM1 nonsynonymous single nucleotide polymorphism rs1799971 (A118G) is the most prominent candidate due to its significant association with onset and treatment of opioid addiction. Marked inter-individual variability in response to available maintenance pharmacotherapies is the common feature observed in individuals with opioid addiction. Several therapies are only effective among subgroups of opioid individuals which indicate that ethnic, environmental factors and genetic polymorphism including rs1799971 may be responsible for the response to treatment. Pharmacogenetics has the potential to enhance our understanding around the underlying genetic, epigenetic and molecular mechanisms responsible for the heterogeneous response of maintenance pharmacotherapies in opioid addiction. A more detailed understanding of molecular, epigenetic and genetic variants especially the implication of OPRM1 A118G polymorphism in an individual may serve as the way forward to address the opioid epidemic. Personalized medicine, which involves developing targeted pharmacotherapies in accordance with individual genetic and epigenetic makeup, are required to develop safe and effective treatments for opioid addiction.

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“…Over the past few decades, numerous OPRM1 splice variants have been isolated by several laboratories [ 8 , 9 , 11 ], proving that the hypothesis is correct. Although the association of these OPRM1 splice variants with the mu subtypes defined by the early pharmacological studies remains unclear, identification and characterization of these OPRM1 splice variants have revolutionized the concept of multiple mu opioid receptors and provided new insight into our understanding of the complex actions of mu opioids [ 9 , 11 , 12 ].…”

Section: Pharmacology and Molecular Biology Of Mu Opioid Receptorsmentioning

confidence: 99%

“…The actions of these mu opioids are primarily mediated through the mu opioid receptor, a G-protein coupled receptor (GPCR) belonging to the class A rhodopsin family. The concept of multiple mu opioid receptors was initially proposed by early pharmacological studies [ 2 , 3 , 4 , 5 , 6 , 7 ] and further supported by identifying an array of alternatively spliced variants from a single-copy mu opioid receptor gene, OPRM1 [ 8 , 9 , 10 , 11 , 12 , 13 ].…”

Section: Introductionmentioning

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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Alternative Pre‐mRNA Splicing of Mu Opioid Receptor Gene

Cited by 3 publications

References 99 publications

Alternative Splicing of Opioid Receptor Genes Shows a Conserved Pattern for 6TM Receptor Variants

Alternative Splicing of Opioid Receptor Genes Shows a Conserved Pattern for 6TM Receptor Variants

<p><em>OPRM1</em> A118G Polymorphisms and Its Role in Opioid Addiction: Implication on Severity and Treatment Approaches</p>

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

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