By using a strategy based on nucleotide sequence homology, we have cloned a cDNA encoding a functional serotonin (5-HI) receptor. The deduced amino acid sequence of the 5--HT7 receptor displays limited homology with that of other 5-HT receptors. In addition to the seven stretches of hydrophobic amino acids that characterize the superfamily of receptors interacting with guanine nudeotide-binding proteins, the 448-aa sequence of the 5-HT7 receptor contains a hydrophobic domain located at its N-terminal end. Genomic analysis indicated the presence of introns interrupting the coding sequence. The 5-HT7 receptor, stably expressed in transfected CHO ceils, bound [3H]5-HT with hh affnity (Kd = 1 nM), like receptors of the 5-HT1 subfamily from which, however, it was dearly distuished by its phaacology.5-HT in nanomolar concentrations stimulated cAMP accumulation in these CHO celis by =40-fold, whereas lysergic acid diethylamide displayed low intrinsic agonist actiity. These various properties differentiate the 5-HT7 receptor from the four other subfamilies of mammalian 5-HT receptors (i.e., the 5-HTi-, 5-HT2-, 5-HT3-, and 5-HT4-like subfamllies) and, therefore, appear to define another receptor subfamily. Northern blot and in situ hybridization analyses showed the 5-HT7 transcripts to be expressed in discrete areas of the limbic brain (e.g., pyramidal hippocampus cells, tenia tecta, amygdaloid, or nmammiary nudei), suggesting that the receptor mediates serotoninergic controls in functions like mood, learning, or neuroendocrine and vegetative behaviors.Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter that exerts its effects mainly in the central nervous and gastrointestinal systems by interacting with a large variety of receptors. These were initially distinguished through the use of traditional pharmacological approaches with isolated organs (1) and, then, in binding studies (2). More recently, with the introduction of molecular biology approaches in the field (3), a wealth of additional 5-HT receptor subtypes could be characterized.Now, it appears that, whereas the 5-HT3 receptor is a ligand-gated ion channel (4), mammalian 5-HT receptors with seven putative transmembrane domains (TMs) and coupled to guanine nucleotide-binding (G) proteins can be divided into three subfamilies, depending on molecular, ligand binding, and effector-coupling properties. Members of the 5-HT1 subfamily [except, perhaps, the preliminarily characterized 5-HT5 receptor (5)-i.e., 5-HT1A (3, 6), 5-HT1B (7-9), 5-HTlD (10-12), 5-HT1E (13), and 5-HT1F (14) receptors-are encoded by intronless genes, display nanomolar affinity for 5-HT, and are negatively coupled to adenylyl cyclase. The 5-HT2 subfamily contains the homologous 5-HT,c (15) andThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. (16) There is evidence, however, for the existence of additional 5-HT receptors. For...

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