Opioid Receptor: Its structure and how it works
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Abstract:
The First and Second Opium Wars were two conflicts caused by the the reaction of China over the illegal exportation of the drug opium by the British government. Opium, also known as poppy tears, is a narcotic drug extracted from the plant Papaver somniferum. This drug causes a sensation of euphoria and pain relief by binding to opioid receptors that exist on cell membranes of neurons and the digestive tract. Opioid receptors (OR) are G‐protein‐coupled receptors (GPCRs) with three main variables, μ‐OR, δ‐OR and κ‐OR. The μ‐OR is the most important opioid receptor for the management of pain. To better understand this receptor's structure and how it can impact function, the Worcester Academy SMART Team has modeled the μ‐OR using 3D printing technology. Using the irreversible antagonist β‐FNA, the μ‐OR has a complex shape, consisting of seven transmembrane α‐helices connected by three extracellular loops and three intracellular loops; transmembrane helices 5 and 6 are involved in receptor dimerization. The binding pocket is relatively open which causes a greater exposure to the extracellular surface, providing evidence as to why potent opioids like buprenorphine and etorphine have a rapid dissociation. β‐FNA interacts with 14 residues, of which nine have more interaction with the ligand and are conserved in the δ‐OR and the κ‐OR. The μ‐OR contains 11 identical amino acid residues with the the other two ORs. The only differences are the positions E229, K303 and W318, which are Asp, Trp and Leu. Further understanding of opioid receptors and their structure can lead to a way of treating pain without side effects.Keywords:
Etorphine
Etorphine
DAMGO
Opioid antagonist
μ-opioid receptor
Diprenorphine
Narcotic antagonists
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Etorphine
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DADLE
Etorphine
Diprenorphine
DAMGO
δ-opioid receptor
μ-opioid receptor
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Opioid receptors mediate multiple biological functions through their interaction with endogenous opioid peptides as well as opioid alkaloids including morphine and etorphine. Previously we have reported that the ability of distinct opioid agonists to differentially regulate μ-opioid receptor (μOR) responsiveness is related to their ability to promote G protein-coupled receptor kinase (GRK)-dependent phosphorylation of the receptor (1). In the present study, we further examined the role of GRK and β-arrestin in agonist-specific regulation of the δ-opioid receptor (δOR). While both etorphine and morphine effectively activate the δOR, only etorphine triggers robust δOR phosphorylation followed by plasma membrane translocation of β-arrestin and receptor internalization. In contrast, morphine is unable to either elicit δOR phosphorylation or stimulate β-arrestin translocation, correlating with its inability to cause δOR internalization. Unlike for the μOR, overexpression of GRK2 results in neither the enhancement of δOR sequestration nor the rescue of δOR-mediated β-arrestin translocation. Therefore, our findings not only point to the existence of marked differences in the ability of different opioid agonists to promote δOR phosphorylation by GRK and binding to β-arrestin, but also demonstrate differences in the regulation of two opioid receptor subtypes. These observations may have important implications for our understanding of the distinct ability of various opioids in inducing opioid tolerance and addiction.
Etorphine
Arrestin
Internalization
μ-opioid receptor
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Opium Poppy
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Diprenorphine
Etorphine
μ-opioid receptor
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DADLE
Etorphine
Seizure threshold
Opioid antagonist
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Etorphine
μ-opioid receptor
Diprenorphine
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Poppy
Accidental
Opium Poppy
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