Functional, molecular and pharmacological advances in 5-HT7 receptor research

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The 5-HT7 receptor was among a group of 5-HT receptors that were discovered using targeted cloning strategies 12 years ago. This receptor is a seven-transmembrane-domain G-protein-coupled receptor that is positively linked to adenylyl cyclase. The distributions of 5-HT7 receptor mRNA, immunolabeling and radioligand binding exhibit strong similarities, with the highest receptor densities present in the thalamus and hypothalamus and significant densities present in the hippocampus and cortex. The recent availability of selective antagonists and knockout mice strains has dramatically increased our knowledge about this receptor. Together with unselective agonists, these new tools have helped to reveal the 5-HT7 receptor distribution in more detail. Important functional roles for the 5-HT7 receptor in thermoregulation, circadian rhythm, learning and memory, hippocampal signaling and sleep have also been established. Hypotheses driving current research indicate that this receptor might be involved in mood regulation, suggesting that the 5-HT7 receptor is a putative target in the treatment of depression.

Section snippets

Pharmacology and knockouts

The availability of selective ligands is of utmost importance to the elucidation of the characteristics and function of a receptor. However, a well-characterized selective agonist for the 5-HT7 receptor is not yet available. Furthermore, the fact that 8-OH-DPAT, previously considered to be the standard selective agonist for the 5-HT1A receptor, has high affinity for the 5-HT7 receptor adds to the confusion regarding which receptor subtype is involved in previously observed phenomena. Most

5-HT7 receptor signaling

Although coupling of the 5-HT7 receptor to cAMP formation has been known since the discovery of the receptor 3, 4, 5, recent studies have elucidated the functional coupling of the 5-HT7 receptor in more detail. At least when expressed in cell lines, the receptor is tightly associated with the G protein, regardless of agonist binding [21]. The receptor activates the extracellular signal-regulated kinase (ERK) through a mechanism that is dependent on a Ras monomeric GTPase [22]. Although ERK

Distribution of the 5-HT7 receptor

Early and more-recent studies in guinea-pigs and rats have used in situ hybridization to determine with increasing resolution where the gene encoding the 5-HT7 receptor is expressed 4, 25, 26, 27. The studies all show that 5-HT7 receptor mRNA is most abundant in the thalamus, hippocampus and hypothalamus. It is noteworthy that 5-HT7 receptor mRNA is present in all of the CA fields of the hippocampus and in the suprachiasmatic nucleus (SCN) of the hypothalamus. Mapping of the expression of the

Thermoregulation

The involvement of 5-HT in thermoregulation is a well-known phenomenon. For example, injection of 5-CT or 8-OH-DPAT induces hypothermia in rodents. The hypothermic effect is similar regardless of whether the drug is administered peripherally or centrally, suggesting a central mechanism of action. Because both 5-CT and 8-OH-DPAT are 5-HT1A receptor agonists, this receptor was generally considered to be the main mediator of the hypothermia, although some reports had suggested the involvement of

Concluding remarks

The availability of selective antagonists and knockout mice has led to an unprecedented activity in 5-HT7 receptor research. As a result, the distribution and functional coupling of the receptor has been determined in more detail and many important roles for the receptor have been identified in thermoregulation, learning and memory, hippocampal activity, endocrine function, sleep, circadian rhythms and mood. Future studies and pharmaceutical development should determine whether a 5-HT7 receptor

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