Different Routes to cAMP

Science's STKE  27 Jun 2006:
Vol. 2006, Issue 341, pp. tw214
DOI: 10.1126/stke.3412006tw214

When treated with nerve growth factor (NGF), the rat PC12 pheochromocytoma cell line extends neurites and differentiates toward a sympathetic neuron-like phenotype, a process that involves activation of the small GTPase (guanosine triphosphatase) Rap1. PACAP (pituitary adenylate cyclase-activating polypeptide) also activates Rap1 and elicits neurite outgrowth in PC12 cells. Rap1 activation by PACAP depends on PACAP's activation of a transmembrane adenylyl cyclase (tmAC), by way of the G protein-coupled receptor PAC1R, and the subsequent production of adenosine 3′,5′-monophosphate (cAMP). The possible role of cAMP in NGF signaling, however, has been controversial, and the route through which NGF might stimulate cAMP signaling has been unclear. Stessin et al. found that, in the presence of a phosphodiesterase inhibitor, NGF elicited an increase in the cAMP content of PC12 cells; chelating intracellular calcium eliminated this increase. Pharmacological inhibition of tmAC with 2′5′-dideoxyadenosine eliminated activation of Rap1 by PACAP but failed to have any effect on NGF-mediated stimulation of Rap1. Treatment with KH7 [which inhibits soluble adenylyl cyclase (sAC)], however, or knockdown of sAC with RNAi, eliminated both the NGF-mediated increase in cAMP and NGF-mediated activation of Rap1 but not the increase in cAMP elicited by PACAP. Thus, the authors propose that NGF-mediated activation of Rap1, like PACAP-mediated activation of Rap1, depends on generation of cAMP but that, unlike PACAP, NGF stimulates cAMP formation through a process that requires sAC activation and is independent of tmAC.

A. M. Stessin, J. H. Zippin, M. Kamenetsky, K. C. Hess, J. Buck, L. R. Levin, Soluble adenylyl cyclase mediates nerve growth factor-induced activation of Rap1. J. Biol. Chem. 281, 17253-17258 (2006). [Abstract] [Full Text]