cAMP promotes neurite outgrowth and extension through protein kinase A but independently of Erk activation in cultured rat motoneurons

It is well established that cAMP counteracts myelin inhibition to permit axon regeneration in the central nervous system. On the other hand, the role of cAMP in axonal growth on permissive substrates remains controversial because the evidence available is contradictory. In view that elevation of cAMP represents an attractive therapeutic target to promote nerve regeneration in vivo, we investigated the effect of cAMP on neurite outgrowth and extension in motoneurons. We manipulated cAMP levels pharmacologically in cultured motoneurons and investigated targets downstream of cAMP of neurite outgrowth and extension on a permissive substrate. Reduction of cAMP by the adenylyl cyclase inhibitor SQ22536 inhibited, and elevation of cAMP by forskolin, dibutyryl cAMP, IBMX and rolipram increased outgrowth and extension of neurites. The cAMP-mediated effects occur via activation of protein kinase A (PKA) and were reduced by the inhibitors, H89 and Rp-cAMP. However, cAMP elevation did not lead to Erk activation that is an essential downstream component of neurotrophin signaling. These findings provide evidence for a key role of cAMP in promoting peripheral nerve regeneration after nerve injuries and indicate that this effect is unusual in not being mediated via Erk phosphorylation.