Multiple signal transduction pathways mediated by 5-HT receptors
Received: 06 June 2003 Accepted: 17 July 2003 DOI:
Cite this article as: Noda, M., Higashida, H., Aoki, S. et al. Mol Neurobiol (2004) 29: 31. doi:10.1385/MN:29:1:31 Abstract
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-HT 1 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. Index Entries 5-HT 5A receptors G i/G o adenylyl cyclase cyclic AMP ADP ribosyl cyclase cyclic ADP ribose IP3 K + channels References
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