Signal transduction differences between 5-hydroxytryptamine type 2A and type 2C receptor systems

The cDNAs for human 5-hydroxytryptamine (5-HT)(2C) and 5-HT(2A) receptors were stably transfected separately into parent Chinese hamster ovary cells, and cell lines in which levels of transfected receptor protein expression and accumulation of inositol phosphates in response to 5-HT were comparable were chosen for study. The effect of activation of these receptors on 5-HT(1B)- like receptor-mediated responsiveness (i.e., inhibition of forskolin- stimulated cAMP accumulation) was studied. Activation of 5-HT(2C) receptors with 5-HT (0.1-100 μM) abolished the 5-HT(1B)-like response, which returned when 5-HT(2C) receptors were blocked with mesulergine (1 μM). Furthermore, the maximal response to 5-carboxytryptamine was reduced in a concentration- dependent manner by the 5-HT(2A)/5-HT(2C)-selective partial agonist (±)-1- (2,5-dimethoxy-4-iodophenyl)-2-aminopropane. In contrast, activation of 5- HT(2A) receptors with either 5-HT or (±)-1-(2,5-dimethoxy-4-iodophenyl)-2- aminopropane did not alter the 5-HT(1B)-like response. The reduction of 5- HT(1B)-like responsiveness produced by 5-HT(2C) receptor activation was independent of protein kinase C activation and increases in the intracellular calcium concentration. Although 5-HT(2A) and 5-HT(2C) receptors are strikingly similar in structure and pharmacology, and the signal transduction systems coupled to these receptors have been thought to be similar, if not identical, these data provide the first evidence for fundamental differences in the signal transduction systems of these 5-HT₂ receptor subtypes.