Multiple signal transduction pathways mediated by 5-HT receptors

Among human serotonin (5-HT) receptor subtypes, each G protein-coupled receptor subtype is reported to have one G protein-signaling cascade. However, the signaling may not be as simple as previously thought to be. 5-HT _5A receptors are probably the least well understood among the 5-HT receptors, but the authors found that 5-HT_5A receptors couple to multiple signaling cascades. When the 5-HT_5A receptors were expressed in undifferentiated C6 glioma cells, they modulated the level of second messengers. For example, activation of 5-HT_5A receptors inhibited the adenylyl cyclase activity and subsequently reduced the cAMP level, as previously reported. In addition to this known signaling via G _i/G_o, 5-HT_5A receptors are coupled to the inhibition of ADP-ribosyl cyclase and cyclic ADP ribose formation. On the other hand, activation of 5-HT_5A receptors transiently opened the K ⁺ channels, presumably due to the increase in intracellular Ca ²⁺ after formation of inositol (1,4,5) trisphosphate. The K ⁺ currents were inhibited by both heparin and pretreatment with pertussis toxin, suggesting the cross-talk between G_i/G_o protein and phopholipase C cascade. Thus, the authors results indicate that 5-HT_5A receptors couple to multiple second messenger systems and may contribute to the complicated physiological and pathophysiological states. Although this multiple signaling has been reported only for 5-HT _5A/5-HT₁ receptors so far, it is possible that other 5-HT receptor subtypes bear similar complexity. As a result, in addition to the wide variety of expression patterns of each 5-HT receptor subtype, it is possible that multiple signal transduction systems may add complexity to the serotonergic system in brain function. The investigation of these serotonergic signaling and its impairment at cellular level may help to understand the symptoms of brain diseases.