Introduction of the 5-HT3B subunit alters the functional properties of 5-HT3 receptors native to neuroblastoma cells

Stewart, Andrew P.; Davies, Paul; Kirkness, Ewen F.; Safa, Parsa; Hales, Tim G.

doi:10.1016/s0028-3908(02)00376-3

Cited by 46 publications

(38 citation statements)

References 28 publications

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“…As previously observed (Davies et al, 1999;Dubin et al, 1999;Stewart et al, 2003), incorporation of h5-HT 3B subunits into heteromeric h5-HT 3 receptors resulted in 5-HTevoked currents that were distinct from those mediated by homomeric h-5HT 3A receptors (Fig. 1B).…”

Section: Resultssupporting

confidence: 84%

Modulation of Human 5-Hydroxytryptamine Type 3AB Receptors by Volatile Anesthetics and n-Alcohols

Stevens¹,

Rüsch²,

Solt³

et al. 2005

J Pharmacol Exp Ther

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Functional 5-hydroxytryptamine type 3 (5-HT 3 ) receptors can be formed by 5-HT 3A subunits alone or in combination with the 5-HT 3B subunit, but only the 5-HT 3A receptor has been previously studied with respect to the modulation by volatile anesthetics and n-alcohols. Using two-electrode voltage-clamp, we show for the first time the modulation of heteromeric human (h)5-HT 3AB receptors, expressed in Xenopus oocytes, by a series of n-alcohols and halogenated volatile anesthetics. At twice their anesthetic concentration, compounds having a molecular volume of less than 110 Å 3 enhanced submaximal 5-HTevoked current. Compounds larger than 110 Å 3 inhibited submaximal 5-HT-evoked current. In experiments examining 5-HT concentration-response relationships, chloroform and butanol caused a slight decrease in the 5-HT EC 50 . Sevoflurane and octanol inhibited 5-HT-evoked current at all 5-HT concentrations tested but had no effect upon the 5-HT EC 50 . Compared with previous data on homomeric h5-HT 3A receptors, the presence of the h5-HT 3B subunit reduces the enhancement of h5-HT 3 receptors by smaller halogenated volatile anesthetics and n-alcohols. In summary, these results suggest that heteromeric h5-HT 3AB receptors are modulated by halogenated volatile anesthetics at clinically relevant concentrations, in addition to n-alcohols, suggesting that these receptors may be another physiological target for these compounds. The modulation is dependent upon the molecular volume of the compound, further supporting the concept of an anesthetic binding pocket of limited volume common on other Cys-loop ligand-gated ion channels. Incorporation of the 5-HT 3B subunit alters either the anesthetic binding site or the allosteric interactions between anesthetic binding and channel opening.

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Section: Resultssupporting

confidence: 84%

Modulation of Human 5-Hydroxytryptamine Type 3AB Receptors by Volatile Anesthetics and n-Alcohols

Stevens¹,

Rüsch²,

Solt³

et al. 2005

J Pharmacol Exp Ther

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“…2B). Consistent with previous reports (Davies et al, 1999;Stewart et al, 2003), 5-HT 3AB receptors were less potently activated by 5-HT (Table 1) and desensitized more rapidly than 5-HT 3A receptors (Fig. 2B).…”

Section: Resultssupporting

confidence: 93%

“…Concentration-response relationships were fitted with a logistic equation (Fig. 2), yielding the parameters provided in this desensitization is a well documented effect of incorporation of the 5-HT 3B subunit (Dubin et al, 1999;Stewart et al, 2003 (Fig. 4B).…”

Section: Resultsmentioning

confidence: 98%

Direct Subunit-Dependent Multimodal 5-Hydroxytryptamine₃Receptor Antagonism by Methadone

Deeb

Sharp²,

Hales

2009

Mol Pharmacol

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Homomeric 5-hydroxytryptamine (5-HT) 3A and heteromeric 5-HT 3AB receptors mediate rapid excitatory responses to serotonin in the central and peripheral nervous systems. The alkaloid morphine, in addition to being a -opioid receptor agonist, is a potent competitive inhibitor of 5-HT 3 receptors. We examined whether methadone, an opioid often used to treat morphine dependence, also exhibited 5-HT 3 receptor antagonist properties. Racemic (R/S)-methadone inhibited currents mediated by human homomeric 5-HT 3A receptors (IC 50 ϭ 14.1 Ϯ 2.5 M). Incorporation of the 5-HT 3B subunit into heteromeric 5-HT 3AB receptors reduced the potency of inhibition by (R/S)-methadone (IC 50 ϭ 41.1 Ϯ 0.9 M). (R/S)-Methadone also increased apparent desensitization of both 5-HT 3 receptor subtypes. The inhibition of the 5-HT 3A receptor was competitive; however, incorporation of the 5-HT 3B subunit caused the appearance of inhibition that was insurmountable by 5-HT. In the absence of rapid desensitization, when dopamine was used as an agonist of 5-HT 3AB receptors, the inhibition by (R/S)-methadone was voltage-dependent. The antagonist and desensitization-enhancing effects of (R/S)-methadone were shared by pure (R)-and (S)-methadone enantiomers, which had similar actions on 5-HT-evoked currents mediated by 5-HT 3 receptors. However, (R)-methadone exhibited a larger voltage-dependent inhibition of dopamine-evoked currents mediated by 5-HT 3AB receptors than did (S)-methadone. Inhibition of 5-HT 3A receptors by (R/S)-methadone was not influenced by voltage. Thus, methadone displays multimodal subunit-dependent antagonism of 5-HT 3 receptors.The 5-hydroxytryptamine (5-HT) type 3 receptor is a ligand-gated cation channel that mediates rapid serotonergic excitatory synaptic transmission (Sugita et al., 1992). It contains binding sites for 5-HT and several allosteric modulators. The 5-HT 3 receptor is a member of the Cys-loop superfamily of pentameric receptors, which also includes the nicotinic acetylcholine, ␥-aminobutyric acid, and glycine receptors, and the Zn 2ϩ -activated ion channel (Barnes et al., 2009). The 5-HT 3A subunit forms homomeric receptors and can also combine into heteromeric receptors with the 5-HT 3B

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“…The hetero-oligomeric 5-HT 3A /5-HT 3B receptor has been reported to contain two copies of the 5-HT 3A subunit and three copies of the 5-HT 3B subunit in the order B-B-A-B-A (Barrera et al, 2005). The 5-HT 3B subunit imparts distinctive biophysical properties upon hetero-oligomeric 5-HT 3A /5-HT 3B versus homo-oligomeric 5-HT 3A recombinant receptors (Davies et al, 1999;Dubin et al, 1999;Hanna et al, 2000;Kelley et al, 2003;Stewart et al, 2003; Peters et al, 2005), but generally has little effect upon the apparent affinity of agonists, or the affinity of antagonists (Brady et al, 2001; but see Dubin et al, 1999). However, 5-HT 3A and 5-HT 3A /5-HT 3B receptors differ in their allosteric regulation by some general anaesthetic agents and small alcohols (Solt et al, 2005;Rüsch et al, 2007).…”

mentioning

confidence: 99%

Transmitter‐Gated Channels

Alexander¹,

Mathie²,

Peters³

2008

British J Pharmacology

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Overview: The 5-HT 3 receptor [nomenclature as agreed by the NC-IUPHAR Subcommittee on 5-hydroxytryptamine (serotonin) receptors (Hoyer et al., 1994)] is a transmitter-gated ion channel of the Cys-loop family that includes the nicotinic acetylcholine, GABA A and strychninesensitive glycine receptors. The receptor exists as a pentamer of 4TM subunits that form an intrinsic cation selective channel. Five human 5-HT 3 receptor subunits have been cloned and homo-oligomeric assemblies of 5-HT 3A and hetero-oligomeric assemblies of 5-HT 3A and 5-HT 3B subunits have been characterised in detail. The recently described 5-HT 3C (ENSG00000178084), 5-HT 3D (ENSG00000186090) and 5-HT 3E (ENSG00000186038) subunits (Karnovsky et al., 2003;Niesler et al., 2003), like the 5-HT 3B subunit, do not form functional homomers, but are reported to assemble with the 5-HT 3A subunit to influence its functional expression rather than pharmacological profile (Niesler et al., 2007). The hetero-oligomeric 5-HT 3A /5-HT 3B receptor has been reported to contain two copies of the 5-HT 3A subunit and three copies of the 5-HT 3B subunit in the order B-B-A-B-A (Barrera et al., 2005). The 5-HT 3B subunit imparts distinctive biophysical properties upon hetero-oligomeric 5-HT 3A /5-HT 3B versus homo-oligomeric 5-HT 3A recombinant receptors (Davies et al., 1999;Dubin et al., 1999;Hanna et al., 2000;Kelley et al., 2003;Stewart et al., 2003; Peters et al., 2005), but generally has little effect upon the apparent affinity of agonists, or the affinity of antagonists (Brady et al., 2001; but see Dubin et al., 1999). However, 5-HT 3A and 5-HT 3A /5-HT 3B receptors differ in their allosteric regulation by some general anaesthetic agents and small alcohols (Solt et al., 2005;Rüsch et al., 2007). The potential diversity of 5-HT 3 receptors is increased by alternatively spliced variants of the 5-HT 3A subunit (Hope et al., 1993;Bruss et al., 2000), and tissue-specific preferences for different transcription start sites in the HTR3B gene, which could result in three different 5-HT 3B subunit N-termini (Tzvetkov et al., 2007). To date, inclusion of the 5-HT 3A subunit appears imperative for 5-HT 3 receptor function.Quantitative data in the table refer to homo-oligomeric assemblies of the human 5-HT 3A subunit, or the receptor native to human tissues. Notably, most ligands display significantly reduced affinities at the guinea-pig 5-HT 3 receptor in comparison with other species. In addition to the agents listed in the table, native and recombinant 5-HT 3 receptors are subject to allosteric modulation by extracellular divalent cations, alcohols, several general anaesthetics and 5-hydroxy-and halide-substituted indoles (see reviews by Parker et al., 1996; Lovinger, 1999; Lummis, 2006, 2007).

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Introduction of the 5-HT3B subunit alters the functional properties of 5-HT3 receptors native to neuroblastoma cells

Cited by 46 publications

References 28 publications

Modulation of Human 5-Hydroxytryptamine Type 3AB Receptors by Volatile Anesthetics and n-Alcohols

Modulation of Human 5-Hydroxytryptamine Type 3AB Receptors by Volatile Anesthetics and n-Alcohols

Direct Subunit-Dependent Multimodal 5-Hydroxytryptamine₃Receptor Antagonism by Methadone

Transmitter‐Gated Channels

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Introduction of the 5-HT3B subunit alters the functional properties of 5-HT3 receptors native to neuroblastoma cells

Cited by 46 publications

References 28 publications

Modulation of Human 5-Hydroxytryptamine Type 3AB Receptors by Volatile Anesthetics and n-Alcohols

Modulation of Human 5-Hydroxytryptamine Type 3AB Receptors by Volatile Anesthetics and n-Alcohols

Direct Subunit-Dependent Multimodal 5-Hydroxytryptamine3Receptor Antagonism by Methadone

Transmitter‐Gated Channels

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Direct Subunit-Dependent Multimodal 5-Hydroxytryptamine₃Receptor Antagonism by Methadone