5-HT3 Antagonist - The 5-HT₃ Receptor

The 5-HT₃ Receptor

The 5-HT₃ (5-HT₃) receptor belongs to the Cys-loop superfamily of ligand-gated ion channels (LGICs) and therefore differs structurally and functionally from all other 5-HT (serotonin) receptors which are G protein-coupled receptors. This ion channel is cation-selective and mediates neuronal depolarization and excitation within the central and peripheral nervous systems. The rapidly activating, desensitizing, inward current is predominantly carried by sodium and potassium ions. 5-HT₃ receptors have a negligible permeability to anions.

The 5-HT₃ receptor consists of five subunits that may be the same (homopentameric 5-HT_3A receptors) or different (heteropentameric receptors, usually consisting of 5-HT_3A and 5-HT_3B receptor subunits).

The subunits surround a central ion channel in a pseudo-symmetric manner (Fig.1). Each subunit comprises an extracellular N-terminal domain, four transmembrane domains (M1-M4) connected by intracellular (M1-M2 and M3-M4) and extracellular loops (M2-M3) and an extracellular C-terminus (Fig.1). The extracellular domain is the site of action of agonists and competitive antagonists because of ligand binding and the transmembrane domain controls the movement of ions across the cell membrane. The human subunits 5-HT_3A and 5-HT_3B have been isolated and as well as sharing 41% amino acid sequence identity the location of their genes are in close proximity on the long arm of chromosome 11. The 5-HT_3C, 5-HT_3D and 5-HT_3E subunits have not been isolated.

Genes that code for the subunits of the 5-HT₃ receptor have been identified. HTR3A and HTR3B for the 5-HT_3A and 5-HT_3B subunits and in addition HTR3C, HTR3D and HTR3E genes encoding 5-HT_3C, 5-HT_3D and 5-HT_3E subunits. The latter three tend to show peripherally restricted pattern of expression, with high levels in the gut. In human duodenum and stomach, for example, 5-HT_3C and 5-HT_3E mRNA might be greater than for 5-HT_3A and 5-HT_3B. There is some evidence to suggest that the 5-HT₃ receptor subunits are an important contribution to the effectiveness of these compounds. In patients treated with chemotherapeutic drugs, certain polymorphism of the HTR3B gene could predict successful antiemetic treatment. This could indicate that the 5-HT3B receptor subunit could be used as biomarker of antiemetic drug efficacy. HTR3C and HTR3E do not seem to form functional homomeric channels, but when co-expressed with HTR3A they form heteromeric complex with decreased or increased 5-HT efficacies. The pathophysiological role for these additional subunits has yet to be identified.