Which agonist properties are important for the activation of 5-HT3A receptors?

Meiboom, M.F.; Barann, Martin; Witten, S.; Groeneveld, Kathrin; Urban, B. W.

doi:10.1016/j.bbamem.2013.06.013

Cited by 4 publications

(4 citation statements)

References 17 publications

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“…1 B). These values were in line with those reported for the wild-type human 5-HT 3 A receptor (EC 50 of 100-200 mM and $27% of maximal response (43)). Thus, our macroscopic characterization indicates that the high-conductance receptor behaves similarly to the wild-type 5-HT 3 A receptor.…”

Section: Activation Of the Human 5-ht 3 A Hc Receptor By Orthosteric And Allosteric Ligands At The Macroscopic Levelsupporting

confidence: 90%

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Orthosteric and Allosteric Activation of Human 5-HT3A Receptors

Araujo

Fabiani

Dimarco

et al. 2020

Biophysical Journal

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The serotonin type 3 receptor (5-HT 3 ) is a ligand-gated ion channel that converts the binding of the neurotransmitter serotonin (5-HT) into a transient cation current that mediates fast excitatory responses in peripheral and central nervous systems. Information regarding the activation and modulation of the human 5-HT 3 type A receptor has been based only on macroscopic current measurements because of its low ion conductance. By constructing a high-conductance human 5-HT 3 A receptor, we here revealed mechanistic information regarding the orthosteric activation by 5-HT and by the partial agonist tryptamine, and the allosteric activation by the terpenoids, carvacrol, and thymol. Terpenoids potentiated macroscopic currents elicited by the orthosteric agonist and directly elicited currents with slow-rising phases and submaximal amplitudes. At the single-channel level, activation by orthosteric and allosteric agonists appeared as openings in quick succession (bursts) that showed no ligand concentration dependence. Bursts were grouped into long-duration clusters in the presence of 5-HT and even longer in the presence of terpenoids, whereas they remained isolated in the presence of tryptamine. Kinetic analysis revealed that allosteric and orthosteric activation mechanisms can be described by the same scheme that includes transitions of the agonist-bound receptor to closed intermediate states before opening (priming). Reduced priming explained the partial agonism of tryptamine; however, equilibrium constants for gating and priming were similar for 5-HT and terpenoid activation. Thus, our kinetic analysis revealed that terpenoids are efficacious agonists for 5-HT 3 A receptors. These findings not only extend our knowledge about the human 5-HT 3 A molecular function but also provide novel insights into the mechanisms of action of allosteric ligands, which are of increasing interest as therapeutic drugs in all the superfamily.

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Section: Activation Of the Human 5-ht 3 A Hc Receptor By Orthosteric And Allosteric Ligands At The Macroscopic Levelsupporting

confidence: 90%

“…We also explored macroscopic activation of human 5-HT 3 A HC receptor by tryptamine, which is a partial agonist of mouse and human 5-HT 3 A receptor (15,43). Compared to 5-HT, tryptamine-elicited currents showed a slower activation phase (Fig.…”

Section: Activation Of the Human 5-ht 3 A Hc Receptor By Orthosteric And Allosteric Ligands At The Macroscopic Levelmentioning

confidence: 99%

Orthosteric and Allosteric Activation of Human 5-HT3A Receptors

Araujo

Fabiani

Dimarco

et al. 2020

Biophysical Journal

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“…Indeed, previous structure-activity studies on arylbiguanides have reported the same affinities for CPB as our own, but did not explore agonist activities (Dukat et al, 1996;Glennon et al, 2003). In these studies, an important role for the 3-position substituent was reported, consistent with the importance of the 3-hydroxyl in the agonists 5-HT, dopamine, m-tyramine, and mCPBG (Meiboom et al, 2013;Thompson and Lummis, 2013). In our own study, the transfer of Cl from the 3-(mCPBG) to the 4-position (CPB) caused a dramatic change in agonist efficacy, consistent with these earlier reports.…”

Section: Proguanil Inhibition Of 5-ht 3 Receptorssupporting

confidence: 71%

The Antimalarial Drug Proguanil Is an Antagonist at 5-HT₃Receptors

Lochner

Thompson

2014

J Pharmacol Exp Ther

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Proguanil is an antimalarial prodrug that is metabolized to 4-chlorophenyl-1-biguanide (CPB) and the active metabolite cycloguanil (CG). These compounds are structurally related to meta-chlorophenyl biguanide (mCPBG), a 5-hydroxytryptamine 3 (5-HT 3 ) receptor agonist. Here we examine the effects of proguanil and its metabolites on the electrophysiology and ligand-binding properties of human 5-HT 3 A receptors expressed in Xenopus oocytes and human embryonic kidney 293 cells, respectively. 5-HT 3 receptor responses were reversibly inhibited by proguanil, with an IC 50 of 1.81 mM.

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“…At a high concentration, binding of 5‐HoI to the orthosteric site or 5‐MoI to the allosteric site of the unliganded R* conformation yields agonism, whereas conformational changes induced by concomitant/subsequent binding of 5‐HoI to the allosteric site (Figure ; Supporting Information http://onlinelibrary.wiley.com/doi/10.1111/bph.12896/suppinfo) or 5‐MoI to the orthosteric site (Figure ; Supporting Information http://onlinelibrary.wiley.com/doi/10.1111/bph.12896/suppinfo) of the liganded R* conformation would promote negative cooperativity and/or reduce efficacy generated by ligand binding to the other site, leading to receptor inactivation. 5‐HT 3 receptor agonists 5‐HT, 1‐(m‐chlorophenyl)‐biguanide (mCPBG) and tryptamine at high concentrations produced an auto‐inhibition at the wild‐type receptor, resulting in bell‐shaped concentration‐response curves (Lankiewicz et al ., ; Hapfelmeier et al ., ; Meiboom et al ., ). This auto‐inhibition may represent a type of non‐competitive, homotropic antagonism, possibly arising from a cross‐talk between orthosteric and allosteric sites upon simultaneous binding by the same ligand.…”

Section: Discussionmentioning

confidence: 97%

Auto‐inhibition at a ligand‐gated ion channel: a cross‐talk between orthosteric and allosteric sites

2014

British J Pharmacology

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BACKGROUND AND PURPOSEA ligand is believed to produce either positive or negative responses, or to block both of them. However, an indole compound was found to promote both positive and negative effects at the 5-HT3AB receptor, which displays a low level of spontaneous activity. The present study attempted to delineate the mechanisms underlying this phenomenon. EXPERIMENTAL APPROACHThe spontaneously active V291S 5-HT3A receptor was used to explore the properties of 5-hydroxyindole (5-HoI) and 5-methoxyindole (5-MoI), structural analogues of 5-HT, either alone or in combination with orthosteric probes. KEY RESULTSTwo types of efficacy switching were initiated by altering ligand structure and concentration. At lower concentrations, a subtle structural change at position 5 of the indole molecule resulted in opposite effects. 5-HoI apparently elicited partial allosteric inverse agonism, whereas 5-MoI induced allosteric agonism. Interestingly, at a higher concentration, these indoles produced distinct auto-inhibition, manifested as a switch from positive to negative effects. 5-HoI induced a transition from orthosteric agonism to allosteric inverse agonism, whereas 5-MoI produced a shift from allosteric agonism to orthosteric inverse agonism. The auto-inhibition appears to involve communication between orthosteric and allosteric sites of the active receptor conformation and/or between inactive and active conformations. An additive effect of orthosteric and allosteric inverse agonism and insensitivity of allosteric agonism to orthosteric antagonism were also demonstrated. CONCLUSIONS AND IMPLICATIONSTogether, the results suggest that the moiety at position 5 of the indole structure is a critical determinant of a ligand's properties at the 5-HT3A receptor, providing new insights into understanding ligand-receptor interactions.Abbreviations 5-HoI, 5-hydroxyindole; 5-MoI, 5-methoxyindole; LGIC, ligand-gated ion channel; nACh receptor, nicotinic ACh receptor; 4,

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Which agonist properties are important for the activation of 5-HT3A receptors?

Cited by 4 publications

References 17 publications

Orthosteric and Allosteric Activation of Human 5-HT3A Receptors

Orthosteric and Allosteric Activation of Human 5-HT3A Receptors

The Antimalarial Drug Proguanil Is an Antagonist at 5-HT₃Receptors

Auto‐inhibition at a ligand‐gated ion channel: a cross‐talk between orthosteric and allosteric sites

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Which agonist properties are important for the activation of 5-HT3A receptors?

Cited by 4 publications

References 17 publications

Orthosteric and Allosteric Activation of Human 5-HT3A Receptors

Orthosteric and Allosteric Activation of Human 5-HT3A Receptors

The Antimalarial Drug Proguanil Is an Antagonist at 5-HT3Receptors

Auto‐inhibition at a ligand‐gated ion channel: a cross‐talk between orthosteric and allosteric sites

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The Antimalarial Drug Proguanil Is an Antagonist at 5-HT₃Receptors