Leading Article: Central & Peripheral Nervous Systems: 5-Hydroxytryptamine (5-HT)₄ receptors: physiology, pharmacology and therapeutic potential

Abstract

The 5-HT₄ receptor is a seven transmembrane spanning, G-protein coupled receptor, that, in all tissues studied to date, positively couples to adenylate cyclase. The receptor exists in two isoforms (5-HT_4S and 5-HT_4L), that differ in their distribution in both central and peripheral nervous systems. Pharmacologically, the 5-HT₄ receptor is defined by several selective agonists and antagonists, some with good bioavailability in a number of species. Selective radioligands are now available for the receptor and these have facilitated the mapping of 5-HT₄ distribution in the brain. Based upon the anatomical location and activity of selective ligands in animal models, emerging data suggest that 5-HT₄ receptors play a role in learning and memory formation. In the periphery, several lines of evidence indicate that the receptor modulates gastrointestinal motility and secretion, increases heart rate, enhances steroid secretion from the adrenal gland and augments bladder emptying. A number of 5-HT₄ receptor agonists, with varying degrees of selectivity, are in clinical development, primarily in terms of their potential to augment gastric motility. Although clinical data are unavailable, it is possible that selective 5-HT₄ receptor antagonists will have therapeutic utility in the treatment of irritable bowel syndrome, urge incontinence or cardiac arrhythmias.

Key Words:

• 5-HT₄ receptor
• selective agonists and antagonists
• cognition
• gastrointestinal tract
• urinary bladder
• adrenal cortex
• myocardium