Stimulation and inhibition of adenylyl cyclase by distinct 5-hydroxytryptamine receptors.
5-Hydroxytryptamine (serotonin, 5-HT) stimulates basal adenylyl cyclase activity in membranes from guinea pig or rat hippocampi, but 5-HT inhibits forskolin-stimulated adenylyl cyclase activity in these same membranes. The opposing effects of 5-HT on adenylyl cyclase activity indicate that distinct 5-HT receptors, positively and negatively coupled to adenylyl cyclase, are present in these membranes. Stimulation of adenylyl cyclase activity is mediated by two distinct 5-HT receptors. The receptor with lower affinity for 5-HT, designated as RL, is apparently homologous with a 5-HT receptor present in rat collicular membranes, but it is not homologous with the stimulatory receptor characterized in neuroblastoma hybrid cell (NCB-20) membranes. The receptor with higher affinity for 5-HT is homologous with the 5-HT1A binding site. The magnitude of stimulation by 5-HT1A receptors is variable with respect to stimulation by RL and is sometimes completely absent. Inhibition of forskolin-stimulated adenylyl cyclase activity, in membranes from either rat or guinea pig hippocampus or rat cortex, is a functional correlate of the 5-HT1A binding site. This inhibitory response was used to determine the pharmacological characteristics of drugs that reportedly have high affinity for 5-HT1A binding sites, such as 1-[2-(4-aminophenyl)ethyl]-4-(3-trifluoromethylphenyl)piperazine (PAPP) and (-)pindolol. PAPP inhibited adenylyl cyclase activity in guinea pig hippocampal membranes with an EC50 value of 27 +/- 3 nM. (-)Pindolol was a partial agonist in inhibiting adenylyl cyclase activity in guinea pig and rat hippocampal membranes. Because of the low intrinsic activity of (-)pindolol, it was tested as an antagonist of the inhibition produced by 5-HT1A receptor agonists in rat hippocampal membranes. The Kb of (-)pindolol was 40 nM as measured by a Schild plot. (-)Propranolol was a simple competitive antagonist at the rat hippocampal receptor with a Kb value of 550 nM. In summary, guinea pig and rat hippocampal membranes possess two distinct populations of 5-HT receptors, a 5-HT receptor that mediates inhibition of adenylyl cyclase activity and is pharmacologically homologous with the 5-HT1A binding site, and a stimulatory receptor that appears to be homologous with the 5-HT receptor first characterized in infant rat collicular membranes.
De Vivo
M
M
Department of Pharmacology, Mount Sinai School of Medicine, City University, New York, NY 10029.
Maayani
S
S
D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects; D002540:Cerebral Cortex / Q000201:enzymology; D005576:Colforsin / Q000494:pharmacology; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D005476:Fluphenazine / Q000494:pharmacology; D006168:Guinea Pigs; D006624:Hippocampus / Q000201:enzymology; D008433:Mathematics; D008803:Mianserin / Q000494:pharmacology; D010869:Pindolol / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D011985:Receptors, Serotonin / Q000494:pharmacology*; D013134:Spiperone / Q000494:pharmacology
D000067956:Adenylyl Cyclase Inhibitors; D010879:Piperazines; D011985:Receptors, Serotonin; D005576:Colforsin; D008803:Mianserin; D013134:Spiperone; C044643:LY 165163; D010869:Pindolol; D000262:Adenylyl Cyclases; D005476:Fluphenazine