5-HT3 receptors

Abstract

The 5-HT(3) receptor is a member of the Cys-loop family of ligand-gated ion channels. These receptors are located in both the peripheral and central nervous systems, where functional receptors are constructed from five subunits. These subunits may be the same (homopentameric 5-HT(3A) receptors) or different (heteropentameric receptors, usually comprising of 5-HT(3A) and 5-HT(3B) receptor subunits), with the latter having a number of distinct properties. The 5-HT(3) receptor binding site is comprised of six loops from two adjacent subunits, and critical ligand binding amino acids in these loops have been largely identified. There are a range of selective agonists and antagonists for these receptors and the pharmacophore is reasonably well understood. There are also a wide range of compounds that can modulate receptor activity. Studies have suggested many diverse potential disease targets that might be amenable to alleviation by 5-HT(3) receptor selective compounds but to date only two applications have been fully realised in the clinic: the treatment of emesis and irritable-bowel syndrome.

Fig. (1)

A homology model of the extracellular and transmembrane domains of the 5-HT₃ receptor. In Fig. (1A), the receptor is shown from the side and the position of the membrane is highlighted as a grey box. In Fig. (1B) the receptor is shown from above, looking down towards the membrane and through the central ion-conducting pore. The structure was created from a fusion of homology models based upon the crystal structure of AChBP (PDB ID; 1i9b) and cryo-electron microscopy of the nAChR (PDB ID; 1oed).

Fig. (2)

M2 channel lining residues from four members of the ligand-gated ion-channel family. Supposed pore lining residues are shown next to the M2 α-helix (PDB ID; 1oed). Members of the family that have been studied using SCAM and SHAM are shown in the alignment below and amino acids that have been identified as accessible to modifying sulfydryl reagents or transition metal cations are highlighted as boxes in the 5-HT₃ [37, 149], ACh [150] and GABA_A [151] receptors. Rings of charged amino acids are located at positions -4′, -1′ and 20′. Accession numbers for the alignment are: 5-HT_3A Q605711, nAChα1 P02710, GABA_A α1 P14867, Glycine α1 P23415.

Fig. (3)

Adjacent subunits (principal and complementary) showing the positions of the main binding loops within the extracellular domain. Only two of the five subunits have been shown for ease of viewing. An alignment of the 5-HT_3A, nAChR α1 and AChBP sequences is shown below. The binding loops of the receptors are indicated by lines above the alignment and their location can be seen in the structure above. The positions of the β-sheets are shown by grey lines beneath the text and are taken from the AChBP protein crystal structure [10]. Accession numbers for the 5-HT_3AR, nAChα1 and AChBP protein sequences are Q6J1J7, P02710 and P58154 respectively.

Fig. (4)

Examples of 5-HT₃ receptor agonists.

Fig. (5)

5-HT₃ receptor agonist and antagonist pharmacophores. 5-HT (Fig. 5A) and granisetron (Fig. 5B) are shown as examples of 5-HT₃ receptor agonists and antagonists. Electrostatic potential is displayed in wire-frame and shows negative potential in red and positive potential in blue. Attention has been drawn to the important features of each pharmacophore.

Fig. (6)

5-HT bound to the ligand-binding site of the 5-HT₃ receptor. Adapted from Reeves et al. 2003 (Model 4, [41]) where a more detailed description of the binding residues can be found.

Fig. (7)

Examples of selective and non-selective 5-HT₃ receptor antagonists.

Fig. (8)

Granisetron bound to the ligand-binding site of the 5-HT₃ receptor. Adapted from Thompson et al., (Model B, [16]) where a more detailed description of the binding residues can be found.