Review
Functional characteristics of heterologously expressed 5-HT receptors

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Abstract

Over the past 10 years, molecular cloning has revealed the presence of 15 serotonin (5-hydroxytryptamine; 5-HT) receptor subtypes, which can be subdivided in seven subfamilies. Except for the 5-HT3 receptors, which are ligand-gated ion channels, all 5-HT receptors belong to the superfamily of G-protein-coupled receptors. The large multiplicity of 5-HT receptor subtypes has been suggested to be a direct result of the evolutionary age of the 5-HT system. Molecular information on G-protein-coupled 5-HT receptors is currently available for several mammalian species as well as for a limited number of invertebrate species (insects, molluscs). The aim of this review is to give an overview of all cloned 5-HT receptor subtypes belonging to the superfamily of G-protein-coupled receptors with specific emphasis on the pharmacological and signaling properties of the receptors upon expression in several heterologous expression systems.

Introduction

Receptors interacting with serotonin (5-hydroxytryptamine; 5-HT) can be classified into seven different subfamilies. All but one, the 5-HT3 receptor, belong to the superfamily of G-protein-coupled receptors. These receptors function by activating a GTP-binding protein (G-protein), that in turn can influence the activity of several membrane-bound effector proteins (second messenger-producing enzymes and ion channels). The six G-protein-coupled 5-HT receptor subfamilies can be distinguished on the basis of their degree of amino acid sequence identity (see Fig. 1) and their coupling to particular signaling pathway(s) (see Table 1). In short, the 5-HT1 receptor subfamily consists of five members, each of which is negatively coupled to adenylyl cyclase. The 5-HT2 receptor subfamily comprises three members, all positively coupled to phospholipase C. The 5-HT4, 5-ht6 and 5-HT7 receptor subfamilies all stimulate adenylyl cyclase, but their pharmacological properties differ considerably. The 5-ht5 receptor subfamily, which contains two members, couples to an as yet unknown signal transduction pathway.

This review presents the functional properties of all members of the 5-HT receptor subfamilies when expressed in a variety of heterologous systems. Emphasis is put on the differences in structure and function between species variants of particular receptor subtypes, or variations in signal transduction pathways activated by the same receptors in different cellular contexts. For the description of 5-HT receptors in endogeneous tissues the reader is referred to a number of extensive reviews (Zifa and Fillion, 1992, Hoyer et al., 1994).

Section snippets

5-HT1 receptor family

5-HT1 receptors form the largest subclass of 5-HT receptor subtypes. Originally, these receptors were grouped together because they share a high affinity for 5-HT and 5-carboxyamidotryptamine (5-CT) and are antagonized by methiothepin and methysergide (Bradley et al., 1986). At present, the defining characteristics of 5-HT1 receptors are their primary sequences, the fact that they do not contain introns in their coding sequence (with the exception of two receptors identified in Drosophila (

5-HT2 receptor family

The 5-HT2 receptor subclass consists of three subtypes: (i) the 5-HT2A receptor, the `classical' 5-HT2 receptor, that is still often referred to as 5-HT2 receptor, (ii) the 5-HT2B receptor, that was formerly called 5-HT2F (F for fundus, because of the high expression level of this particular receptor in the stomach fundus) and (iii) the 5-HT2C receptor; this receptor was originally called 5-HT1C receptor based on its relatively high affinity for 5-HT, but it was later renamed 5-HT2C receptor,

5-HT4 receptors

Effects of 5-HT mediated by 5-HT4 receptors have been described in heart, adrenal, bladder, and alimentary canal (see Bockaert et al., 1992 for a review). Consequently, a role of this receptor subtype in diseases of the gastrointestinal tract, as well as in cardiac, urinary and endocrine functions has been postulated. 5-HT4 receptors have also been found in the brain, especially in the hippocampus, indicating a role in cognitive enhancement.

Two different cDNAs, probably resulting from

-HT5 receptors

As yet, no clear function has been associated to the 5-ht5 receptors. Because of their high affinity for LSD and ergot derivatives, they are postulated to mediate some of the effects of these drugs. Because the chromosomal localization of 5-ht5A receptors (both in mouse and in human), corresponds to regions in which mutations lead to abnormal brain development, it has been suggested that the 5-ht5A receptor is involved in brain development (Matthes et al., 1993). The 5-ht5A and 5-ht5B receptors

5-HT6 receptors

The existence of the 5-ht6 receptor was revealed first by the cloning and characterization of its cDNA. Using this cDNA, the in vivo presence of 5-ht6 receptor-encoding mRNA was confirmed in striatal neurons (Sebben et al., 1994) and in pig caudate putamen membranes (Schoeffter and Waeber, 1995). In addition, the 5-HT receptors that have been characterized in NCB-20 neuroblastoma cells (Conner and Mansour, 1990) and in N18TG2 cells (Unsworth and Molinoff, 1994) might belong to the 5-ht6

Vertebrate 5-HT7 receptors

The 5-HT7 receptors have been implicated in smooth muscle relaxation in various tissues and have been suggested to play a role in affective behaviour sensory processes and regulation of circadian phase shifts (for a recent review see Eglen et al. (1997). The high affinity of the 5-HT7 receptor for neuroleptic agents suggests that this receptor, just like the 5-ht6 receptor, might play a role in certain neuropsychiatric disorders. The affinities of a large body of typical and atypical

Invertebrate 5-HT1-like receptors

Today, the sequence information for three invertebrate 5-HT1-like receptors is known: two receptors from Drosophila melanogaster, (5-HTdro2A and 5-HTdro2B; Saudou et al., 1992) and one receptor from Lymnaea stagnalis (5-HTLym; Sugamori et al., 1993) (see Fig. 1).

The sequence and signaling properties of the 5-HTdro2A and 5-HTdro2B receptors suggest that they belong to the 5-HT1 receptor family. However, their genes do contain at least four introns in the coding region. A specific function has

Conclusions

The period that receptors were looked upon solely as ligand binding sites lies far behind us. The isolation of the genes and/or the cDNAs encoding 5-HT receptors has provided us with a complete new set of tools to study receptors. Firstly, it has become clear that classification of a specific receptor subtype on the basis of pharmacological data does not always lead to unambiguous results. Small differences in receptor structure, sometimes as small as a difference in a single amino acid, have

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    Present address: Institut Cochin de Genetique Moléculaire, Laboratoire d'Immunopharmacologie Moleculaire, 22 Rue Méchain, 75014 Paris, France.

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