Dose–Response Analysis When There Is a Correlation between Affinity and Efficacy

Auerbach, Anthony

doi:10.1124/mol.115.102509

Cited by 16 publications

(11 citation statements)

References 25 publications

(35 reference statements)

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“…In our study, the production of TNF-alpha, TLR4, and CD11c in response to uric acid exhibited a typical dose-response relationship, where a maximum effect is found and, beyond this point, a plateau can be seen, which indicates saturation and the abolishment of the observed effect [47]. The dose-response relationship has been attributed to the interaction between ligand and its receptor [47,48], which suggested to us the possible involvement of a molecule able to transport uric acid inside the macrophage, as is the case of URAT1.…”

Section: Discussionsupporting

confidence: 53%

Uric Acid Has Direct Proinflammatory Effects on Human Macrophages by Increasing Proinflammatory Mediators and Bacterial Phagocytosis Probably via URAT1

et al. 2020

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The relationship of uric acid with macrophages has not been fully elucidated. We investigated the effect of uric acid on the proinflammatory ability of human macrophages and then examined the possible molecular mechanism involved. Primary human monocytes were differentiated into macrophages for subsequent exposure to 0, 0.23, 0.45, or 0.9 mmol/L uric acid for 12 h, in the presence or absence of 1 mmol/L probenecid. Flow cytometry was used to measure proinflammatory marker production and phagocytic activity that was quantified as a percentage of GFP-labeled Escherichia coli positive macrophages. qPCR was used to measure the macrophage expression of the urate anion transporter 1 (URAT1). As compared to control cells, the production of tumor necrosis factor-alpha (TNF-alpha), toll-like receptor 4 (TLR4), and cluster of differentiation (CD) 11c was significantly increased by uric acid. In contrast, macrophages expressing CD206, CX3C-motif chemokine receptor 1 (CX3CR1), and C-C chemokine receptor type 2 (CCR2) were significantly reduced. Uric acid progressively increased macrophage phagocytic activity and downregulated URAT1 expression. Probenecid-a non-specific blocker of URAT1-dependent uric acid transport-inhibited both proinflammatory cytokine production and phagocytic activity in macrophages that were exposed to uric acid. These results suggest that uric acid has direct proinflammatory effects on macrophages possibly via URAT1.

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Section: Discussionsupporting

confidence: 53%

Uric Acid Has Direct Proinflammatory Effects on Human Macrophages by Increasing Proinflammatory Mediators and Bacterial Phagocytosis Probably via URAT1

et al. 2020

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“…Fig. 4 (Bottom) shows log-log plots of K d versus E 1 [a "bindinggating" plot (20)] for the agonists at each site (SI Appendix, Eq. S4).…”

Section: Resultsmentioning

confidence: 99%

“…This indicates that, on average, hold approximately doubles the agonist's binding free energy. As a consequence, on a log-log scale, there is a linear correlation between K d and E 2 , which is the gating equilibrium constant with two bound agonists (20).…”

Section: Significancementioning

confidence: 99%

Cyclic activation of endplate acetylcholine receptors

Nayak

Auerbach

2017

Proc. Natl. Acad. Sci. U.S.A.

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Agonists turn on receptors because they have a higher affinity for active versus resting conformations of the protein. Activation can occur by either of two pathways that connect to form a cycle: Agonists bind to resting receptors that then become active, or resting receptors activate and then bind agonists. We used mutations to construct endplate acetylcholine receptors (AChRs) having only one functional neurotransmitter-binding site and single-channel electrophysiology to measure independently binding constants for four different agonists, to both resting and active conformations of each site. For all agonists and sites, the total free energy change in each pathway was the same, confirming the activation cycle without external energy. Other results show that () there is no cooperativity between sites; () agonist association is slower than diffusion in resting receptors but nearly diffusional in active receptors; () whereas resting affinity is determined mainly by agonist association, active affinity is determined mainly by agonist dissociation; and () at each site and for all agonists, receptor activation approximately doubles the agonist-binding free energy. We discuss a two-step mechanism for binding that involves diffusion and a local conformational change ("catch") that is modulated by receptor activation. The results suggest that binding to a resting site and the switch to high affinity are both integral parts of a single allosteric transition. We hypothesize that catch ensures proper signal recognition in complex chemical environments and that binding site compaction is a determinant of both resting and active affinity.

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“…7 ). Recently, it was suggested that agonist affinity and efficacy might be very tightly related in nicotinic channels 33 . However, our data not only show that this is not the case in AMPA receptors, but provide an intuitive reason why not.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of partial agonism in AMPA-type glutamate receptors

et al. 2017

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Neurotransmitters trigger synaptic currents by activating ligand-gated ion channel receptors. Whereas most neurotransmitters are efficacious agonists, molecules that activate receptors more weakly—partial agonists—also exist. Whether these partial agonists have weak activity because they stabilize less active forms, sustain active states for a lesser fraction of the time or both, remains an open question. Here we describe the crystal structure of an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor (AMPAR) ligand binding domain (LBD) tetramer in complex with the partial agonist 5-fluorowillardiine (FW). We validate this structure, and others of different geometry, using engineered intersubunit bridges. We establish an inverse relation between the efficacy of an agonist and its promiscuity to drive the LBD layer into different conformations. These results suggest that partial agonists of the AMPAR are weak activators of the receptor because they stabilize multiple non-conducting conformations, indicating that agonism is a function of both the space and time domains.

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Dose–Response Analysis When There Is a Correlation between Affinity and Efficacy

Cited by 16 publications

References 25 publications

Uric Acid Has Direct Proinflammatory Effects on Human Macrophages by Increasing Proinflammatory Mediators and Bacterial Phagocytosis Probably via URAT1

Uric Acid Has Direct Proinflammatory Effects on Human Macrophages by Increasing Proinflammatory Mediators and Bacterial Phagocytosis Probably via URAT1

Cyclic activation of endplate acetylcholine receptors

Mechanism of partial agonism in AMPA-type glutamate receptors

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