Opioid Addiction and Opioid Receptor Dimerization: Structural Modeling of the OPRD1 and OPRM1 Heterodimer and Its Signaling Pathways
Autor: | William Hand, Emil Alexov, Bohua Wu |
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Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
medicine.drug_class
QH301-705.5 media_common.quotation_subject Receptors Opioid mu Biology Catalysis Article Inorganic Chemistry δ-opioid receptor Opioid receptor opioid proteins Receptors Opioid delta energy calculations Extracellular medicine Humans Physical and Theoretical Chemistry Biology (General) Molecular Biology Gene QD1-999 Spectroscopy beta-Arrestins media_common Genetics Addiction structural modeling Organic Chemistry General Medicine Opioid-Related Disorders mutations Computer Science Applications Chemistry Opioid Mutation Receptors Opioid μ-opioid receptor Signal transduction Dimerization medicine.drug Signal Transduction opioid addiction |
Zdroj: | International Journal of Molecular Sciences Volume 22 Issue 19 International Journal of Molecular Sciences, Vol 22, Iss 10290, p 10290 (2021) |
ISSN: | 1422-0067 |
DOI: | 10.3390/ijms221910290 |
Popis: | Opioid addiction is a complex phenomenon with genetic, social, and other components. Due to such complexity, it is difficult to interpret the outcome of clinical studies, and thus, mutations found in individuals with these addictions are still not indisputably classified as opioid addiction-causing variants. Here, we computationally investigated two such mutations, A6V and N40D, found in the mu opioid receptor gene OPRM1. The mutations are located in the extracellular domain of the corresponding protein, which is important to the hetero-dimerization of OPRM1 with the delta opioid receptor protein (OPRD1). The hetero-dimerization of OPRD1–OPRM1 affects the signaling pathways activated by opioids and natural peptides and, thus, could be considered a factor contributing to addiction. In this study, we built four 3D structures of molecular pathways, including the G-protein signaling pathway and the β-arrestin signaling pathway of the heterodimer of OPRD1–OPRM1. We also analyzed the effect of mutations of A6V and N40D on the stability of individual OPRM1/OPRD1 molecules and the OPRD1–OPRM1 heterodimer with the goal of inferring their plausible linkage with opioid addiction. It was found that both mutations slightly destabilize OPRM1/OPRD1 monomers and weaken their association. Since hetero-dimerization is a key step for signaling processes, it is anticipated that both mutations may be causing increased addiction risk. |
Databáze: | OpenAIRE |
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