Pharmacological characterization of two 5-hydroxytryptamine receptors coupled to adenylate cyclase in guinea pig hippocampal membranes.
Two 5-hydroxytryptamine (5-HT) receptors mediate stimulation of adenylate cyclase activity in membranes of adult guinea pig hippocampus. The two receptors were characterized with agonists and antagonists and with the aid of computerized curve-fitting procedures. Each receptor mediates about 50% of the maximal response to 5-HT. 5-HT is about 10-fold more potent in eliciting response through one cyclase-linked receptor (RH) than the other (RL). The concentrations of 5-HT that elicit half-maximal response through RH and RL are 43 +/- 6 nM and 414 +/- 53 nM, respectively. 5-Methoxytryptamine (5-MeOT) and 5-HT are approximately equipotent at each receptor. The agonists tryptamine and bufotenine are less potent than 5-HT at both receptors, and each is about 50-fold selective for RH. The two receptors are best discriminated by the agonists 5-carboxamidotryptamine (5-CONH2-T) and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), both of which are selective for RH. 5-CONH2-T is about 7-fold more potent than 5-HT at RH. The rank order of agonist potencies at RH (5-CONH2-T greater than 8-OH-DPAT = 5-HT = 5-MeOT greater than bufotenine greater than tryptamine) differs from that at RL (5-HT = 5-MeOT greater than bufotenine greater than tryptamine = 5-CONH2-T greater than 8-OH-DPAT). Spiperone acts as a simple competitive antagonist at RH, with a dissociation constant of 20 nM, but it is at least 100-fold less potent as an antagonist at RL. The relatively low affinities of the selective 5-HT antagonists ketanserin and MDL 72222 for RH and RL indicate that neither receptor may be classified as the 5-HT2 or as the 5-HT3 (i.e., peripheral neuronal) type. The characteristics of RH suggest that it is a functional correlate of the 5-HT1A-binding site in brain. RL appears not to correspond to a known 5-HT-binding site, but it may be homologous to receptors that mediate 5-HT-stimulated adenylate cyclase activity in other systems such as infant rat colliculi. RH and RL may also mediate stimulation of adenylate cyclase activity by 5-HT in hippocampal membranes of adult rat.
D008735:5-Methoxytryptamine / Q000378:metabolism; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D002027:Bufotenin / Q000378:metabolism; D006168:Guinea Pigs; D006624:Hippocampus / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008433:Mathematics; D008566:Membranes / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000378:metabolism*; D012701:Serotonin / Q000031:analogs & derivatives / Q000378:metabolism; D013134:Spiperone / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000378:metabolism; D014363:Tryptamines / Q000378:metabolism
D011985:Receptors, Serotonin; D013764:Tetrahydronaphthalenes; D014363:Tryptamines; D002027:Bufotenin; D012701:Serotonin; D008735:5-Methoxytryptamine; C030820:tryptamine; D013134:Spiperone; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C047087:5-carboxamidotryptamine; D000262:Adenylyl Cyclases