Allosteric modulation of the 5-HT3 receptor

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5-Hydroxytryptamine type 3 (5-HT3) receptors are ligand-gated ion channels that play important roles in depression, anxiety, substance abuse, emesis, inflammatory pain, spinal nociception, gastrointestinal function, and cardiovascular reflexes. Probably the most studied modulators of 5-HT3 receptors are the high affinity competitive ‘setron’ antagonists typified by ondansetron. However, there exists a broad range of compounds that modulate the 5-HT3 receptor, not through the orthosteric site but by binding to allosteric sites. Most notable are therapeutic compounds ascribed to certain targets but that allosterically modulate 5-HT3 receptors at clinically relevant concentrations.

Research highlights

► Some clinically relevant compounds are allosteric modulators of 5-HT3 receptors. ► Subunit compositions of receptors influence effects of allosteric modulators. ► Heteromeric receptors contain an increased number of potential allosteric sites.

Introduction

The 5-Hydroxytryptamine type 3 (5-HT3) receptor is a member of the Cys-loop ligand-gated ion channel (LGIC) superfamily which includes the nicotinic acetylcholine, γ-aminobutyric acid type A (GABAA), glycine, and ZAC receptor ion channels [1]. Five genes encoding for individual subunits (5-HT3A–E) have been identified within the human genome [2]. However, current knowledge of 5-HT3 receptor pharmacology is heavily biased toward information from human and rodent homomeric 5-HT3A receptors expressed in recombinant cells or native 5-HT3 receptors of unknown subunit composition expressed in rodent cells (rodents have genes only for 5-HT3A and 5-HT3B subunits).

Agonists and positive modulators of 5-HT3 receptors are not favorable for clinical use because of enhanced anxiety and proemetic effects. In contrast, antagonists are successfully used to treat chemotherapy-induced vomiting, postoperative nausea and vomiting (PONV), alcohol craving, and irritable bowel syndrome with diarrhea. Modulators of 5-HT3 receptors have also been suggested to have therapeutic relevance for schizophrenia, anxiety, cognition, and nociception [3].

Most members of the LGIC superfamily have several different subunits that can assemble to form multiple receptor subtypes. Each subunit structurally influences channel properties; hence heteromeric receptors provide diversity in pharmacological and biophysical properties within a receptor family. Allosteric modulators bind to a site distinct from the orthosteric site (the endogenous agonist binding site) but alter receptor conformations that influence the binding and/or functional properties of agonists binding to the orthosteric site. Compared to homomeric receptors, heteromeric receptors contain an increased number of potential allosteric sites for drug interaction.

This review examines clinically relevant allosteric modulators of 5-HT3 receptors, and focuses on compounds that modulate 5-HT3 receptors at physiological concentrations. The current list of compounds is based on work performed almost entirely on homomeric 5-HT3A receptors. With the existence of five genes encoding for 5-HT3 receptor subunits in the human genome, it is inevitable that the known pharmacology of the listed allosteric compounds will change when tested against novel 5-HT3 subunit combinations.

Section snippets

Alcohols and volatile anesthetics

Alcohols and volatile anesthetics can produce an assortment of behavioral effects. Numerous targets have been proposed to explain the effects of alcohols and anesthetics, including the 5-HT3 receptor. Activation of 5-HT3 receptors enhances the release of the neurotransmitters dopamine (DA) and GABA, which are believed to be the principal neurotransmitters for addiction and intoxication, respectively. 5-HT3 receptor antagonists reduce the halothane-mediated inhibition of spinal sensory neuronal

Intravenous anesthetics

In comparison to the potentiation of 5-HT-evoked currents by volatile anesthetics of low molecular volume, intravenous anesthetics have an inhibitory effect on 5-HT3 receptor channels. Various experimental approaches such as 5-HT3 receptor-mediated depolarizations of the rat isolated vagus nerve, currents recorded from oocytes and HEK293 cells expressing 5-HT3 receptors or rodent cell lines with native 5-HT3 receptors have been employed to study intravenous anesthetic modulation of 5-HT3

Antidepressants and antipsychotics

The therapeutic endpoints of antidepressants are often stated to increase the levels of neurotransmitters by various mechanisms. However, there is increasing awareness that antidepressants associate with 5-HT3 receptors, resulting in an allosteric inhibition. Fan [21] showed in rat neurons that imipramine (tricyclic), fluoxetine (selective serotonin reuptake inhibitor, SSRI), phenelzine, and iproniazid (monoamine oxidase inhibitors, MAOI) inhibit 5-HT3 receptor-mediated currents.

At low,

Cannabinoids

Both natural (Δ9-THC and anandamide) and synthetic (WIN55,212-2, JWH-015, and CP55940) cannabinoids (CBs) have been shown to efficiently suppress nausea and vomiting and to exhibit analgesic properties [27]. However, these CB compounds have limited therapeutic potential due to their psychotropic actions mediated by their agonistic profile at CB receptors. In addition, CBs inhibit 5-HT3 receptors.

Anandamide exhibited a high potency for the block of human 5-HT3 receptors compared to its Ki for

Other compounds

A number of other compounds have been shown to modulate 5-HT3 receptors. These include local anesthetics; lidocaine and bupivacaine which are both competitive and allosteric antagonists at the 5-HT3A receptor [31]. Steroids are noncompetitive inhibitors of 5-HT3 receptors, but only at concentrations that exceed physiological concentrations [2]. Morphine, hydromorphone, and fentanyl have been shown to cause a competitive block of 5-HT3A receptors [32, 33]. Methadone, an opioid often used to

Kinetic mechanisms of 5-HT3A receptor modulation

So how do the allosteric compounds modulate 5-HT-elicited current amplitudes and shift 5-HT concentration response curves? We have recently developed a kinetic model (Figure 2) [35] that defines agonist-evoked activation of 5-HT3A receptors. Agonist (A) binds to the closed, resting state of the receptor (R) and the agonist-bound receptor (AR) then transitions to an open channel state (AO). From the open state the receptor can desensitize (AD) or, if the agonist is removed, can close either

Polymorphisms of 5-HT3 receptors influence pharmacology

In recent years an increasing amount of literature has been published detailing the occurrence and influence of 5-HT3 subunit polymorphisms in a number of pathological states. Some polymorphisms alter channel kinetics [36], which may influence the binding and/or action of allosteric compounds such that they alter the effectiveness and side effects of some therapeutic compounds. Therapeutic responses to and side effects of the SSRI paroxetine are influenced by variants in the 5-HT3A subunit and

Future aspects

Most studies to date have been performed on homomeric 5-HT3A receptors, usually performed on expressed rodent subunits and at room temperature. Rodents have only two orthologs of the five genes that encode human 5-HT3 subunit genes. It has been noted that rodents do not make good models for gastrointestinal research [44]. If rodents are not a good model for 5-HT3 receptor mechanisms in the ‘little brain’ then perhaps the rodent is an unsatisfactory model for learning about 5-HT3 receptor

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgement

The author is supported by a grant from the National Institutes of Health National Institute of Alcoholism and Alcohol Abuse [Grant R21-AA017938].

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