Human serotonin 5‐HT7 receptor: cloning and pharmacological characterisation of two receptor variants

Two splice variants of the 5-HT7 receptor were identified in human brain that differ in the lengths of their intracellular carboxy terminal tail. Identification of the variants of this receptor is of particular interest since the 5-HT7 receptor is known to have a high affinity for a number of antidepressan ts and is localized in brain regions thought to be implicated in depression. The two isoforms are expressed in roughly equal amounts in various regions of the human brain. When expressed in NIH-3T3 cells, both variants encode functional 5-HT7 receptors, positively coupled to adenylyl cyclase. We suggest that both variants are derived from a single gene by alternative mRNA splicing. Furthermore, our results from Southern blot analysis studies suggest that additional 5-HT7 receptor genes may exist in human. © 1997 Federation of European Biochemical Societies. receptor has been identified in the human population (6,7). The most extensive polymorphism is a 48-bp tandem repeat located within the third cytoplasmic loop of the receptor (6,7). In this study we report the cloning of two cDNAs for 5- HT 7 receptor variants from human brain. The identification of variants of the 5-HT7 receptor subtype is of particular interest since this receptor is thought to be localized to limbic and cortical regions of the brain (8-12). Moreover, this recep- tor shows a high affinity for serotonin as well as for a number of tricyclic antipsychotic and antidepressant drugs (8-12). The existence of a variant of this receptor in human brain may have therapeutical implications for the treatment of psychiat- ric diseases. We show that the two isoforms are co-expressed at similar levels in various brain regions. Furthermore, using ligand-binding and functional studies we show that both ver- sions of the receptor encode functional receptors that increase adenylyl cyclase activation. 2. Materials and methods