AGONIST-INDUCED DOWN-REGULATION OF HUMAN 5-HT(1A) AND 5-HT(2) RECEPTORS IN SWISS 3T3 CELLS

WE have used single cell clones of Swiss 3T3 cells transfected with ge nes for the human 5-HT1A or 5-HT2 receptor to study down-regulation an d desensitization. After preincubation of the cells with serotonin ago nists, a time-dependent decrease in [H-3]8-hydroxy-2-(di-n-propylamino ) tetralin or [H-3]ketanserin binding was observed. The pertussis toxi n sensitive, 5-HT mediated inhibition of forskolin-stimulated cAMP acc umulation in 5-HT1A receptor transfected cells was diminished by 68% a fter a 2 h pre-incubation of the cells with 1 0 muM 5-HT. The pertussi s toxin insensitive, 5-HT mediated PI turnover in 5-HT2 receptor trans fected cells was decreased by 65% after pre-treatment. While this decr ease was paralleled by a decreased potency of 5-HT to stimulate PI tur nover, in 5-HT1A cells the potency of 5-HT to inhibit cAMP formation w as comparable to control values. The down-regulation and desensitizati on of the 5-HT2 receptor can be explained by phosphorylation via activ ated PKC. In contrast, the attenuation of the 5-HT1A receptor-coupled inhibition of cAMP accumulation has to occur by an alternative, as yet unknown, molecular mechanism.