Serotonin (5-Hydroxytryptamine; 5-HT): Receptors

Seven-transmembrane G-protein-coupled and ion channel receptors, through which 5-hydroxytryptamine (5-HT; serotonin) produces its wealth of physiological and pathological effects, have been the subject of intense investigation over the past 50 years. Advances have been made since the pioneering days of isolated organ studies by Gaddum and Picarelli and radioligand studies by Peroutka and Synder; more recently, new data have been developed using molecular techniques, cloning, and in situ hybridization, and a superfamily of 5-HT receptor subtypes has emerged. To bring parental control to this growing family, the International Union of Basic and Clinical Pharmacology Receptor Nomenclature Committee has embraced advances in molecular biology, producing an evolving classification of 5-HT receptors subtypes that has been adopted into the 5-HT family. The basic premise is that three fundamental properties of a receptor are required to be described to ensure a comprehensive classification, which is based on operational (drug-related), transductional (receptor-coupling), and structural (primary amino acid sequence) characteristics. When applied to the currently recognized 5-HT receptors, these criteria indicate the existence of up to seven receptor classes, with isoforms existing for many of the receptor subtypes in the central and peripheral nervous system. To date, the success of the pharmaceutical industry in identifying 5-HT subtype-selective compounds has been remarkable in providing a tool-kit of compounds and drugs to further characterize these receptors; this has led to major clinical advances in psychiatric, neurological, and gastrointestinal disorders, with yet more clinical opportunities awaiting investigation. This article focuses on the 5-HT receptor family members and their localization, pharmacological properties, functional role, and major contribution to clinical practice.