MOLECULAR-BIOLOGY OF THE 5-HT(1) RECEPTOR SUBFAMILY

Four serotonin receptor clones have now been isolated and characterized. They encode the serotonin 5-HT1A, 5-HT1C, 5-HT1D, and 5-HT2 receptors. The serotonin 5-HT1C receptor, which was originally classified as a 5-HT1 receptor, is now seen to be a member of the 5-HT2 receptor subfamily. Within the current 5-HT1 receptor subfamily, the two clones that have been described (5-HT1A and 5-HT1d) show similarities in amino acid sequence and function but are not as closely related as might have been expected. The human 5-HT1D receptor clone, when expressed in mouse fibroblast cells, displays pharmacological binding properties in agreement with human cortical membrane preparations. Sumatriptan, a new antimigraine medication, exhibits an apparent dissociation constant of 3.4 nM at this human receptor site. This represents the highest affinity interaction yet identified for this drug, and suggests that significant species differences may exist in the binding of this compound to 5-HT1D receptors. Similar species differences in ergot drug affinities have been described for the 5-HT2 receptor. Deduced amino acid sequence homologies between serotonin and other monoamine receptor clones are discussed, leading to a classification scheme for serotonin receptors involving superfamily, family, and subfamily relationships.