01 Jul 2003

In this month's Nature Cell Biology,Frank Lezoualc'h and colleagues at the University of South Paris report that serotonin, or 5-hydroxy tryptamine (5HT), mediates sAPPα release through a cyclic AMP (cAMP) signaling pathway independent of protein kinase A (PKA).The study expands on a finding published two years ago which revealed that serotonin can induce the secretion of soluble AβPPα (Aβ precursor protein α) from hamster cells.

Activation of one variant of serotonin receptor, the 5HT4 receptor, can lead to activation of PKA by cAMP. However, first author Marjorie Maillet and colleagues found that addition of the PKA inhibitor H89 to Chinese hamster ovary (CHO) cells expressing 5HT4 failed to attenuate 5HT-mediated secretion of sAPPα. So the authors turned their attention to other possible targets of cAMP.

First, they tested the CHO cells with a cAMP analogue that cannot activate PKA. The analogue did stimulate sAPPα secretion, suggesting that the 5HT pathway can indeed bypass the kinase. As cAMP-mediated activation of Rho and Cdc42 depends on PKA, the authors asked if the other well-known cAMP target, Rac, may mediate sAPPα secretion.

To test this hypothesis. Maillet added 5HT to the CHO cells, then measured the levels of Rac isoforms. She found that Rac was indeed activated in these cells and also in primary neurons and human neuroblastoma cells in response to 5HT.

But what mediates the cAMP activation of Rac? It has been shown that in addition to activation of PKA, cAMP can also activate a family of guanine nucleotide exchange factors called Epac. The latter are also known to activate Rap1, which like Rac is involved in the regulation of secretory processes. Could cAMP-mediated activation of Rap1 and Rac deliver a double whammy that stimulates secretion of sAPPα? Maillet's evidence suggests this is a likely scenario. The authors found that Rap1 is also activated by 5HT in primary neuronal cultures, and that Rac is activated by a constitutively active form of Epac. Finally, both the latter and a dominant active form of Rap1 lead to increased sAPPα secretion.—Tom Fagan.