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 GABA_A 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.

Keywords::

• 5-HT₃
• alosetron
• Cys-loop receptor
• dolasetron
• emesis
• granisetron
• irritable bowel syndrome
• ondansetron
• palonosetron
• ramosetron
• tropisetron

Acknowledgements

Work carried out in the authors’ laboratory is supported by the Wellcome Trust. SCR Lummis is a Wellcome Trust Senior Research Fellow in Basic Biomedical Science.