Intrinsic relative activities of κ opioid agonists in activating Gα proteins and internalizing receptor: Differences between human and mouse receptors
Autor: | Frederick J. Ehlert, Lee-Yuan Liu-Chen, Kelly M. DiMattio |
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Rok vydání: | 2015 |
Předmět: |
Arrestins
Ligands Beta-1 adrenergic receptor Mice Models Receptors Functional selectivity Psychology 5-HT5A receptor Species difference Pharmacology & Pharmacy Protease-activated receptor 2 beta-Arrestins Pediatric Neurotransmitter Agents Tumor Pharmacology and Pharmaceutical Sciences Endocytosis GTP-Binding Protein alpha Subunits Cell biology Interleukin-21 receptor Cognitive Sciences Drug Interleukin 1 receptor type I Protein Binding Signal Transduction medicine.medical_specialty Artificial Intelligence and Image Processing Opioid Biology Behavioral Science & Comparative Psychology Transfection Models Biological Article Cell Line Dose-Response Relationship δ-opioid receptor Species Specificity Kappa opioid receptor Internal medicine Cell Line Tumor Enzyme-linked receptor medicine Animals Humans kappa Pharmacology Dose-Response Relationship Drug Receptors Opioid kappa Neurosciences Biological Endocrinology Guanosine 5'-O-(3-Thiotriphosphate) Ligand bias |
Zdroj: | European journal of pharmacology. 761 |
ISSN: | 1879-0712 |
Popis: | Several investigators recently identified biased κ opioid receptor (KOP receptor) agonists. However, no comprehensive study of the functional selectivity of available KOP receptor agonists at the human and mouse KOP receptors (hKOP receptor and mKOP receptor, respectively) has been published. Here we examined the ability of over 20 KOP receptor agonists to activate G proteins and to internalize the receptor. Clonal neuro-2a mouse neuroblastoma (N2a) cells stably transfected with the hKOP receptor or mKOP receptor were used. We employed agonist-induced [(35)S]GTPγS binding and KOP receptor internalization as measures of activation of G protein and β-arrestin pathways, respectively. The method of Ehlert and colleagues was used to quantify intrinsic relative activities at G protein activation (RAi-G) and receptor internalization (RAi-I) and the degree of functional selectivity between the two [Log RAi-G - logRAi-I, RAi-G/RAi-I and bias factor]. The parameter, RAi, represents a relative estimate of agonist affinity for the active receptor state that elicits a given response. The endogenous ligand dynorphin A (1-17) was designated as the balanced ligand with a bias factor of 1. Interestingly, we found that there were species differences in functional selectivity. The most striking differences were for 12-epi-salvinorin A, U69,593, and ICI-199,441. 12-Epi-salvinorin A was highly internalization-biased at the mKOP receptor, but apparently G protein-biased at hKOP receptor. U69,593 was much more internalization-biased at mKOP receptor than hKOP receptor. ICI199,441 showed internalization-biased at the mKOP receptor and G protein-biased at the hKOP receptor. Possible mechanisms for the observed species differences are discussed. |
Databáze: | OpenAIRE |
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