Selection of distinct conformational states of the 5‐HT<sub>3</sub> receptor by full and partial agonists

Hooft, Johannes A. van; Vijverberg, Henk P.M.

doi:10.1111/j.1476-5381.1996.tb15269.x

Cited by 55 publications

(39 citation statements)

References 37 publications

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“…In the case of DA-induced desensitization, DA dissociates from desensitized receptors nearly two orders of magnitude faster than 5-HT, and the rate-limiting step leading to recovery is the D 3 R transition. Because of its more rapid dissociation rate, DA has a lower affinity for the desensitized (and open) state than 5-HT, consistent with previous studies showing that DA has a higher IC 50 than 5-HT for inducing 5-HT 3 receptor desensitization (van Hooft and Vijverberg, 1996).…”

Section: Discussionsupporting

confidence: 78%

Differential Effects of Serotonin and Dopamine on Human 5-HT_3AReceptor Kinetics: Interpretation within an Allosteric Kinetic Model

Solt

Ruesch²,

Forman³

et al. 2007

J. Neurosci.

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Serotonin type 3 (5-HT 3 ) receptors are members of the pentameric Cys-loop superfamily of receptors that modulate synaptic neurotransmission. In response to agonist binding and unbinding, members of this superfamily undergo a series of conformational transitions that define their functional properties. In this study, we report the results of electrophysiological studies using rapid solution exchange designed to characterize and compare the actions of the high-efficacy agonist serotonin and the low-efficacy agonist dopamine on human 5-HT 3A receptors expressed in human embryonic kidney HEK293 cells. In the case of serotonin, receptor activation rates varied with agonist concentration, and deactivation occurred as a single-exponential process with a rate that was similar to the maximal rate of desensitization. Receptors recovered slowly from long desensitizing pulses of serotonin with a sigmoidal time course. In the case of dopamine, receptor activation rates were independent of agonist concentration, receptor deactivation occurred as a complex process that was significantly faster than the maximal rate of desensitization, and recovery from desensitization occurred more quickly than with 5-HT and its time course was not sigmoidal. We developed an allosteric kinetic model for 5-HT 3A receptor activation, deactivation, desensitization, and resensitization. Interpretation of our results within the context of this model indicated that the distinct modulatory actions of serotonin versus dopamine are largely attributable to the vastly different rates with which these two agonists induce channel opening and dissociate from open and desensitized states.

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Section: Discussionsupporting

confidence: 78%

Differential Effects of Serotonin and Dopamine on Human 5-HT_3AReceptor Kinetics: Interpretation within an Allosteric Kinetic Model

Solt

Ruesch²,

Forman³

et al. 2007

J. Neurosci.

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“…Oocytes were continuously superfused with external solution containing 115 mM NaCl, 2.5 mM KCl, 1. , 50 nl of a 50 mM BAPTA [bis(2-aminophenoxy)ethane-N, N,NЈ,NЈ-tetraacetic acid] solution was injected into oocytes during the experiments via a third micropipette by using a Drummond microinjector. All agonists used were applied at near maximum-effective concentrations (5,12).…”

Section: Methodsmentioning

confidence: 99%

Promiscuous coassembly of serotonin 5-HT ₃ and nicotinic α4 receptor subunits into Ca ²⁺ -permeable ion channels

Hooft

Spier

Yakel

et al. 1998

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

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Serotonin (5-hydroxytryptamine) type 3 receptors (5-HT 3 R) and nicotinic acetylcholine receptors are structurally and functionally related proteins, yet distinct members of the family of ligand-gated ion channels. For most members of this family a diversity of heteromeric receptors is known at present. In contrast, known 5-HT 3 R subunits are all homologs of the same 5-HT 3 R-A subunit and form homopentameric receptors. Here we show, by heterologous expression followed by immunoprecipitation, that 5-HT 3 R and nicotinic acetylcholine receptor ␣4 subunits coassemble into a novel type of heteromeric ligand-gated ion channel, which is activated by 5-HT. The Ca 2؉ permeability of this heteromeric ion channel is enhanced as compared with that of the homomeric 5-HT 3 R channel. Heteromeric 5-HT 3 ͞␣4 and homomeric 5-HT 3 Rs have similar pharmacological profiles, but distinct sensitivities to block by the antagonist d-tubocurarine. Coassembly of subunits beyond the boundaries of ligand-gated ion channel families may constitute an important mechanism contributing to the diverse properties and functions of native neurotransmitter receptors.Through molecular cloning a plethora of subunits of ligandgated ion channels has been identified. In heterologous expression systems, the coassembly of related subunits permits formation of a vast repertoire of neurotransmitter receptors, each with its own characteristic properties. A focus in contemporary neuroscience is to understand the functional significance of the variety of cloned subunits for the diverse properties and functions of native neurotransmitter receptors. For serotonin (5-hydroxytryptamine) type 3 receptors (5-HT 3 R), little molecular diversity has become apparent: only a single class of 5-HT 3 R subunit has been cloned (1-3), and these subunits form homomeric receptors with similar functional properties in heterologous expression systems (4, 5). Conversely, studies of native receptors, indicating substantial heterogeneity of 5-HT 3 R properties, suggest the existence of additional subunits involved in the formation of heteromeric 5-HT 3 Rs (6-9).Ligand-gated ion channels share homology in their primary and predicted secondary structures. A particularly close relationship between 5-HT 3 R and nicotinic acetylcholine receptors (nAChR) has been demonstrated by the construction of a functional chimeric receptor, containing the ligand-binding domain of the nAChR ␣7 and the ion channel domain of the 5-HT 3 R subunits (10). Because of the close resemblance between 5-HT 3 and nAChR subunits, we examined whether the 5-HT 3 R subunit can coassemble with nAChR subunits to form heteromeric receptors. MATERIALS AND METHODSExpression and Recording from Xenopus Oocytes. Oocytes from mature specimens of Xenopus laevis were harvested, injected, and incubated as described before (11). cDNA encoding the 5-HT 3 R-A and cDNAs encoding the ␣2, ␣3, ␣4, ␣7, ␤2, and ␤4 nAChR subunits were injected into the nucleus either alone or pairwise at a ratio of 1:3 5-HT 3 R-A͞nAChR cDNA (t...

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“…Whether this difference is specific for these two PAMs or constitutes a fundamental type I versus II distinction remains to be elucidated. It should also be noted that the process of ␣7 current recovery from desensitization is complex and involves dissociation of ligand from multiple sites and conformational state transitions (Palma et al, 1996;van Hooft and Vijverberg, 1996). Any given PAM may, hence, affect the on and off rates of the agonist, in addition to its onand off-rate kinetics and the conformational transitions in the basal-open-desensitized triad, including reversal of desensitized receptors favoring the open active state.…”

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confidence: 99%

In Vitro Pharmacological Characterization of a Novel Allosteric Modulator of α7 Neuronal Acetylcholine Receptor, 4-(5-(4-Chlorophenyl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide (A-867744), Exhibiting Unique Pharmacological Profile

Malysz¹,

Grønlien²,

Anderson³

et al. 2009

J Pharmacol Exp Ther

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Targeting ␣7 neuronal acetylcholine receptors (nAChRs) with selective agonists and positive allosteric modulators (PAMs) is considered a therapeutic approach for managing cognitive deficits in schizophrenia and Alzheimer's disease. In this study, we describe a novel type II ␣7 PAM, 4-(5-(4-chlorophenyl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide (A-867744), that exhibits a unique pharmacological profile. In oocytes expressing ␣7 nAChRs, A-867744 potentiated acetylcholine (ACh)-evoked currents, with an EC 50 value of ϳ1 M. At highest concentrations of A-867744 tested, ACh-evoked currents were essentially nondecaying. At lower concentrations, no evidence of a distinct secondary component was evident in contrast to 4-naphthalen-1-yl-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonic acid amide (TQS), another type II ␣7 PAM. In the presence of A-867744, ACh concentration responses were potentiated by increases in potency, Hill slope, and maximal efficacy. When examined in rat hippocampus CA1 stratum radiatum interneurons or dentate gyrus granule cells, A-867744 (10 M) increased choline-evoked ␣7 currents and recovery from inhibition/desensitization, and enhanced spontaneous inhibitory postsynaptic current activity. A-867744, like other ␣7 PAMs tested [1-(5-chloro-2-hydroxyphenyl)-3-(2-chloro-5-trifluoromethyl-phenyl)urea (NS1738), TQS, and 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl)-urea (PNU-120596)], did not displace the binding of [ 3 H]methyllycaconitine to rat cortex ␣7* nAChRs. However, unlike these PAMs, A-867744 displaced the binding of the agonist 3 H]A-585539 in an ␣7/5-hydroxytryptamine 3 (␣7/5-HT 3 ) chimera, suggesting an interaction distinct from the ␣7 N terminus or M2-3 loop. In addition, A-867744 failed to potentiate responses mediated by 5-HT 3〈 or ␣3␤4 and ␣4␤2 nAChRs. In summary, this study identifies a novel and selective ␣7 PAM showing activity at recombinant and native ␣7 nAChRs exhibiting a unique pharmacological interaction with the receptor.Neuronal nicotinic acetylcholine receptors (nAChRs) belong to the pentameric superfamily of ligand-gated ion channels that includes 5-HT 3 , GABA A/C , and glycine receptors. These receptors are composed of either homomeric ␣ or hetThis work was supported by Abbott. All authors are employees of Abbott. Article, publication date, and citation information can be found at

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Selection of distinct conformational states of the 5‐HT₃ receptor by full and partial agonists

Cited by 55 publications

References 37 publications

Differential Effects of Serotonin and Dopamine on Human 5-HT_3AReceptor Kinetics: Interpretation within an Allosteric Kinetic Model

Differential Effects of Serotonin and Dopamine on Human 5-HT_3AReceptor Kinetics: Interpretation within an Allosteric Kinetic Model

Promiscuous coassembly of serotonin 5-HT ₃ and nicotinic α4 receptor subunits into Ca ²⁺ -permeable ion channels

In Vitro Pharmacological Characterization of a Novel Allosteric Modulator of α7 Neuronal Acetylcholine Receptor, 4-(5-(4-Chlorophenyl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide (A-867744), Exhibiting Unique Pharmacological Profile

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Selection of distinct conformational states of the 5‐HT3 receptor by full and partial agonists

Cited by 55 publications

References 37 publications

Differential Effects of Serotonin and Dopamine on Human 5-HT3AReceptor Kinetics: Interpretation within an Allosteric Kinetic Model

Differential Effects of Serotonin and Dopamine on Human 5-HT3AReceptor Kinetics: Interpretation within an Allosteric Kinetic Model

Promiscuous coassembly of serotonin 5-HT 3 and nicotinic α4 receptor subunits into Ca 2+ -permeable ion channels

In Vitro Pharmacological Characterization of a Novel Allosteric Modulator of α7 Neuronal Acetylcholine Receptor, 4-(5-(4-Chlorophenyl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide (A-867744), Exhibiting Unique Pharmacological Profile

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Selection of distinct conformational states of the 5‐HT₃ receptor by full and partial agonists

Differential Effects of Serotonin and Dopamine on Human 5-HT_3AReceptor Kinetics: Interpretation within an Allosteric Kinetic Model

Differential Effects of Serotonin and Dopamine on Human 5-HT_3AReceptor Kinetics: Interpretation within an Allosteric Kinetic Model

Promiscuous coassembly of serotonin 5-HT ₃ and nicotinic α4 receptor subunits into Ca ²⁺ -permeable ion channels