The subdivision of HT receptors started
The subdivision of 5-HT receptors started in the 1950s by Gaddum and colleagues, when they realised that in the guinea pig ileum, the effects of 5-HT could be blocked in part by morphine (M), and in part by dibenzyline (D). Gaddum and Picarelli proposed two receptor classes, 5-HT M and 5-HT D (1957). Although non-selective tools were used, the concept proved to be correct. In 1976, when after many painful attempts at monoamine receptor binding, the first radioligand-binding studies succeeded using [3H]5-HT and [3H]LSD, Fillion and colleagues suggested the existence of 5-HT receptors in brain labeled with [3H]5-HT and [3H]LSD (1976, 1977, 1978, 1979); however these papers did not get the deserved attention of the community. Then in 1979, Peroutka and Snyder described two classes of brain 5-HT receptors, using [3H]-5-HT, [3H]-spiperone (a dopaminergic ligand), and [3H]-LSD called 5-HT1 ([3H]-5-HT binding) and 5-HT2 ([3H]-spiperone), with [3H]-LSD labeling both classes. Interestingly, Gaddum's M receptor was still distinct from the 5-HT1 and 5-HT2 receptors in both function and distribution, whereas the D receptor resembled pharmacologically the 5-HT2 binding site; it was also assumed for quite some time that the 5-HT M receptor was purely peripheral, as amply documented in functional studies, and most of the 5-HT stems from chromaffin cells in the gut, whereas in the brain much of the serotonin comes from the raphé nuclei. Thus, Phillip Bradley convened a party in charge of unifying the 5-HT receptor concept and nomenclature. Bradley et al.  proposed the existence three families of 5-HT receptors, named 5-HT1-like (there was already suggestions for diversity of this group from radioligand binding and autoradiographic studies), 5-HT2 and 5-HT3, the latter corresponding to the M receptor. The proposal was based primarily on functional criteria, since radioligand binding was still not convincing to many colleagues, second messenger studies were less popular than today, and no GPCR had been cloned at the time that party congregated from 1984 on; nevertheless, the Bradley nomenclature represented a useful classification framework. However, with the increasing use of radioligand binding in membranes and cells, autoradiography in brain slices and second messenger studies in cells and tissue, subtypes of 5-HT1 receptor ABH australia were further described (5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, 5-ht1E). It became rapidly evident that the 5-HT1C receptor found in the choroid plexus (although labeled with high affinity by [3H]-5-HT), is closer the 5-HT2 receptor family, due to similar pharmacological profiles and 2nd messenger features (stimulation of inositol phosphate production and calcium signalling), and this suggested the existence of 5-HT2 receptor subtypes as well. Further, another 5-HT receptor which had been identified in the mid 1980's in the gastrointestinal tract, heart and brain, was termed 5-HT4 by Saxena and colleagues (see ), but this proposal was initially rejected. Fortunately, in 1986–1988, the molecular biology era started with the cloning of the 5-HT1A receptor (interestingly, G21 as the 5-HT1A receptor was called when it was still an orphan, allowed the cloning of further beta adrenoceptors by homology, see , ). Rapidly, most known but also some unsuspected 5-HT receptors were cloned. This work led to the identification of a number of ‘new’ receptors, devoid of immediate physiological counterparts. Tentatively termed 5-ht1E, 5-HT1F, 5-HT2F, 5-HT5A, 5-HT5B, 5-HT6, and 5-HT7, they required integration into an acceptable classification scheme. As is known now, all 5-HT receptors that belong to the GPCR are part of the type A family of GPCRs and show still significant sequence homology with rhodopsin, but also adrenergic and dopaminergic receptors, and contain the famous DRY motif in the third transmembrane spanning region. Based on these new findings and yet a constantly evolving field, the Serotonin Club Receptor Nomenclature Committee proposed a new nomenclature system based on operational, structural and transductional information (, see Table 1). These principles were subsequently applied to a number of receptor families by the newly created Receptor Nomenclature Committee of the International Union of Pharmacology (NC-IUPHAR), keeping in mind that some historical features will have to be acknowledged at least transiently (for instance the reclassification of opiate receptors met quite some resistance and we are left with the former mu, delta and kappa opiate receptor classes). The current classification (; Hoyer et al. ) is flexible and intended to be adapted, as information from both recombinant and native systems becomes available; however it favours an alignment of nomenclature with the human genome to avoid species differences (see , ). Seven families of 5-HT receptors form the basis of the classification, based on pharmacology, transduction and structure, although one could argue that structure must be predominant as it governs function and ultimately pharmacological signature. One orphan receptor, called 5-HT1P by Gershon and co-workers, present in the gut , is not structurally characterized, and it remains to be seen whether this receptor is a homomer (new) or possibly a heterodimer composed of already known receptors. 5-HT3 receptors are ligand-gated ion channels, thus the 5-HT receptor family is showing similar diversity as do the acetylcholine or glutamate receptors families, which act through both metabotropic receptors and some fast acting ligand-gated channels. The 5-HT system has long been known to regulate emotions, behavioral control and cognition in a very complex manner, as has become evident from a great number of animal and human studies (see ); and that complexity may not be too surprising given the number of players involved in the 5-HT system which includes a multiplicity of receptors, transporters and metabolizing enzymes.