CLONING OF A NOVEL HUMAN SEROTONIN RECEPTOR (5-HT7) POSITIVELY LINKEDTO ADENYLATE-CYCLASE

An intron-containing gene encoding a novel human serotonin (5-HT) rece ptor was isolated from human genomic and cDNA libraries with probes di rected to transmembrane regions of the adenylate cyclase stimulatory D rosophila serotonin receptor gene, 5-HT(dro1). Membranes harvested fro m transiently transfected Cos-7 cells displayed high affinity (K(d) = 8.5 nM), saturable (B(max) = 6 pmol/mg protein) [H-3]5-HT binding. The rank order of potencies for serotonergic ligands to displace specific [H-3]5-HT binding was: 5-carboxamido-tryptamine > methiothepin > mete rgoline > 5-HT > 8-hydroxy-2-(di-n-propylamino)tetralin > sumatriptan > ketanserin > zacopride. 5-HT produced a dose-dependent (EC50 = 992 n M) stimulation (almost-equal-to 20-fold) of cAMP accumulation in trans iently transfected cells, and this response was antagonized by the non selective 5-HT antagonist methiothepin. RNA for this gene was predomin antly detected in the human brain and a subset of peripheral tissues i ncluding coronary artery and several tissues of the gastrointestinal t ract. The molecular biological and pharmacological properties of this receptor suggest that it is the first member of a new serotonin recept or subfamily (5-HT7). The second messenger coupling, and tissue distri bution indicate a possible identity to 5-HT receptors that mediate rel axant responses in certain isolated blood vessels.