Serotonin type 3 (5-HT(3)) receptors are pentameric ion channels belonging to the superfamily of Cys-loop receptors. Receptor activation either leads to fast excitatory responses or modulation of neurotransmitter release depending on their neuronal localisation. 5-HT(3) receptors are known to be expressed in the central nervous system in regions involved in the vomiting reflex, processing of pain, the reward system, cognition and anxiety control. In the periphery they are present on a variety of neurons and immune cells. 5-HT(3) receptors are known to be involved in emesis, pain disorders, drug addiction, psychiatric and GI disorders. Progress in molecular genetics gives direction to personalised medical strategies for treating complex diseases such as psychiatric and functional GI disorders and unravelling individual drug responses in pharmacogenetic approaches. Here we discuss the molecular basis of 5-HT(3) receptor diversity at the DNA and protein level, of which our knowledge has greatly extended in the last decade. We also evaluate their role in health and disease and describe specific case-control studies addressing the involvement of polymorphisms of 5-HT3 subunit genes in complex disorders and responses to drugs. Furthermore, we focus on the actual state of the pharmacological knowledge concerning not only classical 5-HT(3) antagonists--the setrons--but also compounds of various substance classes targeting 5-HT(3) receptors such as anaesthetics, opioids, cannabinoids, steroids, antidepressants and antipsychotics as well as natural compounds derived from plants. This shall point to alternative treatment options modulating the 5-HT(3) receptor system and open new possibilities for drug development in the future.
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