CLONING AND EXPRESSION OF A 5-HYDROXYTRYPTAMINE(7) RECEPTOR POSITIVELY COUPLED TO ADENYLYL-CYCLASE

A cDNA clone (designated as GP2-7) encoding a novel 5-hydroxytryptamin e (5-HT) receptor was isolated from a guinea pig hippocampal library. The receptor shares amino acid homology within the hydrophobic domains with other cloned 5-HT receptor subtypes (34-48%). The sequence of GP 2-7 is homologous to that described for a novel receptor previously cl oned from a rat brain cDNA library and provisionally designated as 5-H T7. mRNA for GP2-7 was detected in cortical and limbic brain regions. Transiently expressed GP2-7 showed high-affinity binding to [H-3]5-HT (pK(i) = 9.0) with the following rank order of affinities: 5-carboxyam idotryptamine (5-CT) > 5-HT = 5-methoxytryptamine (5-MeOT) > methiothe pin > 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT) > spiperone much greater than sumatriptan. Adenylyl cyclase activity in CHO-KI cells t ransiently transfected with GP2-7 was stimulated by several analogues of 5-HT with the following order of potency: 5-CT > 5-HT = 5-MeOT > di propyl-5-CT > 8-OH-DPAT. Methiothepin and spiperone were potent antago nists. Preliminary analysis suggests that GP2-7 closely resembles a re ceptor in the guinea pig hippocampus that exhibits a high affinity tow ard 5-CT.