General Anesthetic-Induced Channel Gating Enhancement of 5-Hydroxytryptamine Type 3 Receptors Depends on Receptor Subunit Composition

Solt, Ken; Stevens, Renna J.; Davies, Paul; Raines, Douglas E.

doi:10.1124/jpet.105.090621

Cited by 40 publications

(34 citation statements)

References 24 publications

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“…In addition, the peak amplitudes of currents evoked by high concentrations of DA were only 15.7 Ϯ 0.4% of those evoked by high concentrations of 5-HT. This is consistent with previous studies using 5-HT 3A receptors expressed in Xenopus oocytes, indicating that DA is a partial agonist of 5-HT 3A receptors (Lovinger et al, 2000;Solt et al, 2005).…”

Section: Activation Of Human 5-ht 3a Receptorssupporting

confidence: 82%

“…In addition to 5-HT, the neurotransmitter dopamine (DA) can activate 5-HT 3 receptors. Studies using oocyte electrophysiological techniques indicate that, in contrast to 5-HT, DA gates 5-HT 3 receptors with low efficacy because peak currents evoked by receptor-saturating concentrations of DA are significantly smaller than those evoked by 5-HT (Lovinger et al, 2000;Solt et al, 2005). These studies also show that the potency of DA is one to two orders of magnitude lower than that of 5-HT.…”

Section: Introductionmentioning

confidence: 59%

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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: Activation Of Human 5-ht 3a Receptorssupporting

confidence: 82%

Section: Introductionmentioning

confidence: 59%

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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“…These studies found that both anesthetics exert at least some of their modulating effects on GABA A receptors by enhancing channel gating. More recently, the potentiating effects of small volatile anesthetics on 5-HT 3A and 5-HT 3AB were studied electrophysiologically using DA (Solt et al, 2005). The results of that study parallel our findings with alcohols in the present study: 1) volatile anesthetics potentiate receptor function by enhancing gating efficacy, and 2) gating enhancement is dependent on receptor subunit composition with the magnitude of gating enhancement being greater in 5-HT 3A relative to 5-HT 3AB receptors.…”

supporting

confidence: 79%

“…The 5-HT and DA concentration ranges were chosen based on previous studies (Solt et al, 2005;Stevens et al, 2005a,b). The duration of 5-HT and DA application was varied from 15 to 60 s, depending upon the concentration of agonist studied, to achieve a peak current response.…”

Section: Experimental Protocolsmentioning

confidence: 99%

Subunit-Dependent Modulation of the 5-Hydroxytryptamine Type 3 Receptor Open-Close Equilibrium by n-Alcohols

Rüsch¹,

Musset²,

Wulf³

et al. 2007

J Pharmacol Exp Ther

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5-Hydroxytryptamine (5-HT, serotonin) type 3 (5-HT 3 ) receptors belong to the alcohol-sensitive superfamily of Cys-loop ligandgated ion channels, and they are thought to play an important role in alcoholism. Alcohols with small molecular volumes increase the amplitude of currents evoked by low 5-HT concentrations and shift the 5-HT concentration-response curve for 5-HT 3 receptor activation leftward, indicative of increased receptor sensitivity to agonist. This action is significantly smaller when currents are mediated by heteromeric 5-HT 3AB receptors compared with homomeric 5-HT 3A receptors. In this study, we used the highly inefficacious 5-HT 3 receptor agonist dopamine to determine whether this difference between 5-HT 3A and 5-HT 3AB receptors reflects differential alcohol modulation of agonist binding affinity or channel gating efficacy. Human recombinant 5-HT 3A and 5-HT 3AB receptors were expressed in Xenopus oocytes, and currents were measured in the absence and presence of alcohols using the two-electrode voltageclamp technique. Modulation by alcohols of peak currents elicited by maximally activating concentrations of dopamine was alcohol concentration-dependent. Potentiation by smaller alcohols was consistently significantly greater in 5-HT 3A than in 5-HT 3AB receptors, whereas inhibition by larger alcohols was not. A representative small (butanol) and large (octanol) alcohol failed to alter the EC 50 value for channel activation by dopamine. We conclude that the presence of the 5-HT 3B subunit in 5-HT 3AB receptors significantly reduces the enhancement of gating efficacy by small alcohols without altering the inhibitory actions of large alcohols.The 5-hydroxytryptamine (5-HT, serotonin) type 3 (5-HT 3 ) receptor is a pentameric cation channel belonging to the anesthetic-sensitive superfamily of Cys-loop ligand-gated ion channels that also includes the nicotinic acetylcholine receptor, GABA A receptor, and glycine receptor. Five human 5-HT 3 receptor subunits (A, B, C, D, and E) have been cloned (Maricq et al., 1991;Davies et al., 1999;Dubin et al., 1999;Karnovsky et al., 2003;Niesler et al., 2003). However, only the 5-HT 3A and the 5-HT 3B subunit have been shown to form functional receptors. Furthermore, whereas 5-HT 3A subunits can form functional homomeric receptors, 5-HT 3B subunits must combine with 5-HT 3A subunits to form functional heteromeric receptors. In general, 5-HT 3A receptors are more widely distributed in the central nervous system than 5-HT 3AB receptors. Expression of the latter has been detected by some (Davies et al., 1999;Dubin et al., 1999;Monk et al., 2001;Reeves and Lummis, 2006) but not all (Morales and Wang, 2002) studies in specific areas of the mammalian brain with strongest expression found in the amygdala and the hippocampus. 5-HT 3 receptors are thought to play an important role in alcoholism (McBride et al., 2004), and clinical studies have shown that 5-HT 3 receptor antagonists are effective at reducing the craving for alcohol, the number of drinking episo...

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“…It has been proposed that these compounds stabilize the open state of 5-HT 3A channels (Zhou and Lovinger, 1996;Zhou et al, 1998;Lovinger et al, 2000;Solt et al, 2005). However, this hypothesis could never be directly measured due to the small single-channel conductance of the 5-HT 3A receptor.…”

mentioning

confidence: 99%

Ethanol Stabilizes the Open State of Single 5-Hydroxytryptamine_3A(QDA) Receptors

Feinberg-Zadek

Davies²

2010

J Pharmacol Exp Ther

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Ethanol enhancement of 5-hydroxytryptamine (5-HT) 3A receptor-mediated responses may have important consequences in the intoxicating and addictive properties of ethanol. Although the exact mechanism is unknown, ethanol-mediated enhancement of 5-HT 3 receptor current has been proposed to occur due to stabilization of the open-channel state. It has not been possible to directly measure the open state of the channel due to the extremely low single-channel conductance of 5-HT 3A channels. Recently, three arginine residues within the large intracellular loop of the 5-HT 3A subunit were substituted by their equivalent residues (glutamine, aspartate, and alanine) of the 5-HT 3B subunit to produce a 5-HT 3A (QDA) subunit that forms functional homomeric channels exhibiting a measurable single-channel conductance. Using whole-cell rapid-agonist application techniques and the cell-attached single-channel recording configuration, we examined human 5-HT 3A (QDA) receptors expressed in human embryonic kidney 293 cells. The agonist sensitivity, macroscopic kinetics, and modulation by ethanol were similar between mutant and wild-type channels, suggesting the substitutions had not altered these channel structure-function properties. The open time histogram for single-channel events mediated by 5-HT 3A (QDA) receptors in the presence of maximal 5-HT was best fit by three exponentials, but in the presence of ethanol a fourth open state was evident. In summary, the QDA substitution greatly enhanced singlechannel conductance with little effect on 5-HT 3A channel's kinetic properties and ethanol enhances agonist action on 5-HT 3A receptors by inducing a new, long-lived open-channel state. Furthermore, the 5-HT 3A (QDA) receptor appears to be suitable for pharmacological studies of 5-HT 3A receptor modulation at a single-channel level.

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General Anesthetic-Induced Channel Gating Enhancement of 5-Hydroxytryptamine Type 3 Receptors Depends on Receptor Subunit Composition

Cited by 40 publications

References 24 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

Subunit-Dependent Modulation of the 5-Hydroxytryptamine Type 3 Receptor Open-Close Equilibrium by n-Alcohols

Ethanol Stabilizes the Open State of Single 5-Hydroxytryptamine_3A(QDA) Receptors

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General Anesthetic-Induced Channel Gating Enhancement of 5-Hydroxytryptamine Type 3 Receptors Depends on Receptor Subunit Composition

Cited by 40 publications

References 24 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

Subunit-Dependent Modulation of the 5-Hydroxytryptamine Type 3 Receptor Open-Close Equilibrium by n-Alcohols

Ethanol Stabilizes the Open State of Single 5-Hydroxytryptamine3A(QDA) Receptors

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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

Ethanol Stabilizes the Open State of Single 5-Hydroxytryptamine_3A(QDA) Receptors