The molecular basis of the structure and function of the 5-HT 3 receptor: a model ligand-gated ion channel (Review)

Abstract

The ligand-gated ion channel superfamily of neurotransmitter receptors are proteins responsible for rapid transmission of nerve impulses at the synapse and have, therefore, been the subject of intensive research for many years. The cys-loop family, of which the 5-HT3 receptor is a member, includes the nicotinic acetylcholine receptor, the GABAA receptor and the glycine receptor. A diverse range of endogenous and artificial ligands activate these receptors, but, nevertheless, the family shares many similarities of structure and function. Several important questions, however, still remain to be determined, including the mechanism of agonist recognition at the binding site, the nature of the connection between the agonist binding and channel domains, the structure of the transmembrane regions and the mechanism of ion permeation and selectivity. This article reviews recent advances in the characterization of the molecular properties of the 5-HT3 receptor and their role in its function, and assesses its suitability as a model system for the study of the above questions.

The Role of Tyrosine Residues in the Extracellular Domain of the 5-Hydroxytryptamine3 Receptor

“…5); thus, it is not surprising that changing it to serine or alanine in the 5-HT 3 native aromatic, phenylalanine, resulted in changed functional receptor characteristics (an ϳ10-fold increase in EC 50 ) but not in binding affinity (K d not significantly different from WT), thus supporting a role for the hydroxyl group in receptor gating. Extensive site-directed mutagenesis of the residue at this location has shown that it is important in the nACh receptor (39), the ␥-aminobutyric acid A receptor (40), and the glycine receptor (41), although there is some debate as to whether it affects the binding affinity (42) or the gating constant (43).…”

“…Among the different family members, the 5-HT 3 1 receptor has the closest functional homology with the nicotinic acetylcholine (nACh) receptor. The nACh receptor is particularly well characterized, because although no high resolution x-ray crystal structure is known, a vast array of techniques including chemical modification, sitedirected mutagenesis, electron microscopy, and molecular modeling have provided a reasonable understanding of the structure-function relationships of the receptor.…”

The L293 residue in transmembrane domain 2 of the 5-HT3A receptor is a molecular determinant of allosteric modulation by 5-hydroxyindole

“…The 5-hydroxytryptamine (serotonin) type 3 (5-HT 3 ), nicotinic acetylcholine (nACh), γ-aminobutyric acid type A (GABA A ), and glycine receptors belong to the Cys-loop ligand-gated ion channel superfamily, which mediate synaptic transmission and modulate neurotransmitter release (Ortells & Lunt, 1995;Reeves & Lummis, 2002). Members of the superfamily are pentamers formed by assembly of one (homomeric) or different (heteromeric) subunits.…”

A Role for the β1-β2Loop in the Gating of 5-HT3Receptors

“…Serotonin 5-HT 3 receptors (5-HT 3 R) are members of the Cys loop receptor superfamily of ligand-gated ion channels (Reeves and Lummis, 2002) that includes the GABA A , glycine, and nicotinic acetylcholine receptors (AChR). 5-HT 3 R antagonists are used clinically for the prevention and amelioration of nausea and emesis (Costall and Naylor, 2004).…”