THE HUMAN 5-HYDROXYTRYPTAMINE 1A RECEPTOR DIFFERENTIALLY MODULATES PHOSPHOLIPASE-C AND ADENYLYL-CYCLASE ACTIVITIES

In this study, we quantitate and compare the ability of the 5-hydroxyt ryptamine 1A (5-HT1A) receptor to modulate the activities of phospholi pase C and adenylyl cyclase as a function of receptor concentration. W e used a single clonal cell line permanently expressing the human 5-HT 1A receptor, and progressively depleted the receptor concentration usi ng an alkylating antagonist lyloxy)-2'-hydroxypropyl-Z-1,8-diamino-p-m enthane, (+/-) Pindobind). For serotonin-induced phospholipase C stimu lation, reductions in receptor number result in dose response curves t hat shift downward and rightward, reflecting both a decreasing maximal effect as well as an increasing ED(50). In contrast, depletion of mor e than 95% of the receptors has no effect on the maximal inhibition of forskolin stimulated adenylyl cyclase activity. Moreover, at all rece ptor concentrations, the amount of serotonin required to produce half maximal phospholipase C stimulation is several fold more than that req uired to produce half maximal inhibition of adenylyl cyclase activity. We conclude that the 5-HT1A receptor modulates these two pathways dif ferently, and that the overall response to challenge with serotonin, i n terms of both phosphatidyl inositol hydrolysis and cyclic AMP produc tion, is dependent upon receptor number.