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
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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