CommentaryAn allosteric model for benzodiazepine receptor function
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Allosteric interactions via the orthosteric ligand binding sites in a constitutive G-protein-coupled receptor homodimer
2021, Pharmacological ResearchAdministration of the benzodiazepine midazolam increases tau phosphorylation in the mouse brain
2019, Neurobiology of AgingCitation Excerpt :As those previous studies involving the acute administration of sedatives used even more profound levels of sedation than that observed with midazolam, our present findings suggest that midazolam possesses a much greater capacity to directly increase the duration of tau phosphorylation than these two commonly used intravenous hypnotic agents, having an effect long after its sedative effect has disappeared. As a benzodiazepine, midazolam produces many of its effects by allosterically binding to the benzodiazepine receptor on GABAA receptors, which in turn potentiates the action of GABA on this receptor subtype (Ehlert et al., 1983; Sigel and Baur, 1988). Previous studies have demonstrated that activation of GABAA receptor using the benzodiazepine desalkylflurazepam (an active metabolite of flurazepam), increased AT8 tau phosphorylation in vitro but had no effect on TG3 (pSer231) or PHF13 (pSer396) (Nykanen et al., 2012).
Quantifying gpcr allostery and biased signaling
2019, GPCRs: Structure, Function, and Drug DiscoveryAiming for allosterism: Evaluation of allosteric modulators of CB<inf>1</inf> in a neuronal model
2015, Pharmacological ResearchCitation Excerpt :Allosteric modulation is not a new idea. For instance several important classes of drugs are allosteric modulators at GABAA receptors (e.g. benzodiazepines [5]). However the first two CB1 NAMs, ORG27569 and PSNCBAM-1 were characterized less than 10 years ago [6–9], while the first CB1 PAM has been described more recently [10].
What ligand-gated ion channels can tell us about the allosteric regulation of G protein-coupled receptors
2013, Progress in Molecular Biology and Translational ScienceCitation Excerpt :The foregoing two-state model is highly constrained, and it behaves similarly to that of the model for ligand-gated ion channels (Fig. 7.8), notwithstanding differences related to the number of orthosteric and allosteric sites per receptor, which are both equal to one for the allosteric ternary complex model in Fig. 7.14. It predicts that a negative allosteric modulator would inhibit the effects of all orthosteric agonists, with the affinity and efficacy components of the modulation being greater for agonists and partial agonists, respectively.1,104,105 Analogous behavior applies to positive allosteric modulators.
Ghrelin receptor. High constitutive activity and methods for developing inverse agonists
2010, Methods in EnzymologyCitation Excerpt :An antagonist reduces the action of an agonist and can be competitive (same binding site than the agonist), noncompetitive (different binding site), or neutral (same affinity for both active and inactive state of the receptor). Constitutive activity was first discovered for ionotropic receptors, such as GABAa receptors (Ehlert et al., 1983). Since then, basal activity was observed for several GPCRs (Leurs et al., 1998).
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Present address: Department of Pharmacology, School of Medicine, University of California, Los Angeles, CA 90024, U.S.A.