REGULATED SECRETION Rac and Rap1 Regulate Soluble Amyloid Precursor Protein Secretion

Maillet et al. determined that regulation of secretion of nonamyloidogenic soluble amyloid precursor protein (sAPP) was mediated by a novel signal transduction pathway involving crosstalk between the Ras and Rho families of small guanosine triphosphatases (GTPases). Activation of the Gs-coupled serotonin (5-HT₄) receptor stimulated sAPP release in Chinese hamster ovary (CHO) cells transfected to express both human 5-HT₄ receptors and a human APP and in primary cultures of mouse cortical neurons. [Gs are the family of heterotrimeric guanine nucleotide-binding protein (G protein) subunits that stimulate adenylyl cyclase.] Pharmacologic analysis indicated that 5-HT₄-mediated sAPP secretion involved cyclic adenosine 3',5'-monophosphate (cAMP), but was independent of protein kinase A (PKA). Similarly, 5-HT₄-mediated activation of the Rho GTPase Rac (assessed by the fraction of GTP-bound Rac to total Rac) through a mechanism that involved cAMP but was independent of PKA. Further pharmacologic analysis, combined with expression of various mutants of Rac, the Ras GTPase Rap1, and Epac1 (cAMP-activated guanine nucleotide exchange factor for Rap1), indicated that cAMP stimulated Epac1, which activated Rap1, which led to activation of Rac and sAPP secretion. These data thus define a novel cAMP-dependent pathway involved in the regulation of sAPP secretion.

M. Maillet, S. J. Robert, M. Cacquevel, M. Gastineau, D. Vivien, J. Bertoglio, J. L. Zugaza, R. Fischmeister, F. Lezoualc'h, Crosstalk between Rap1 and Rac regulates secretion of sAPP. Nat. Cell. Biol. 5 633-639 (2003). [Online Journal]