The 5-HT3 receptor as a therapeutic target

Abstract

The 5-HT3 receptor is a neurotransmitter-gated ion channel. It is a member of the Cys-loop family of receptors, which also includes nicotinic acetylcholine, glycine and GABAA receptors. Each member of the family consists of an arrangement of five subunits surrounding a central ion-conducting pore. The 5-HT3 receptor binding site is composed of six loops from two adjacent subunits, and the critical ligand binding residues within these loops are well documented. There are a range of 5-HT3 receptor agonists and competitive antagonists, but it is the antagonists that dominate their clinical use. Studies have proposed a range of disease symptoms that might be amenable to 5-HT3 receptor selective compounds; however, so far only the treatment of emesis and irritable bowel syndrome have been fully realised. In this review, the authors look at the structure, function and distribution of 5-HT3 receptors and how this may influence their role in disease. The authors also describe the existing clinical applications of 5-HT3 antagonists and the future potential of these drugs.

Figure 1. A schematic representation of a typical Cys-loop receptor subunit

The diagram at the lower left is a cross-section of the transmembrane region shown from above and demonstrates how five subunits associate to form a central ion-conducting pore that is lined by M2 α-helices. Attention is drawn to six loops that form the binding ligand binding site (A – F), regions associated with ion-selectivity (dark lines either side of M2) and the region that has been shown to influence ion conductivity (R-R-R).

Figure 2. A homology model of the extracellular, transmembrane and intracellular domains of the 5-HT₃ receptor

A. The receptor is shown from the side and the position of the membrane is shown as a grey box. So far, the only resolved structure within the intracellular domain of each subunit is an α-helix. B. The receptor is shown from above, looking down towards the membrane and through the central ion-conducting pore. A. and B. are homology models based on cryo-electron microscopy images of the nACh receptor at 4 Å resolution (PDB ID; 2bg9). C. A homology model of the extracellular domains of two adjacent subunits (principal and complementary). This model was based on the crystal structure of AChBP at 2.7 Å (PDB ID; 1i9b) and highlights the six loops that converge to form the ligand binding site. Only two of the five subunits have been shown for ease of viewing. 5-HT (green) and granisetron (red) are docked into the binding site. The positions of these ligands is based upon the most likely orientations taken from [23] and [24]. AChBP: Acetylcholine binding protein; 5-HT: 5-Hydroxytryptamine; nACh: Nicotinic acetylcholine receptor; PDB: Protein DataBank.

Figure 3. Molecular structures of commercially available 5-HT₃ receptor antagonists