Abstract
In Schwann cells (SCs), cyclic adenosine monophosphate (cAMP) not only induces differentiation into a myelinating SC-related phenotype, but also synergistically enhances the mitogenic action of growth factors such as neuregulin. To better understand the molecular mechanism by which cAMP exerts these apparently contradictory functions, we investigated the role of the two main effectors of cAMP, protein kinase A (PKA) and the exchange protein activated by cAMP (EPAC), on the proliferation and differentiation of both isolated and axon-related SCs. For these studies, a variety of PKA and EPAC agonists and antagonists were used, including pathway-selective analogs of cAMP and pharmacological inhibitors. Our studies indicated that the activity of PKA rather than EPAC was required for the adjuvant effect of cAMP on S-phase entry, whereas the activity of EPAC rather than PKA was required for SC differentiation and myelin formation. Even though selective EPAC activation had an overall anti-proliferative effect in SCs, it failed to drive the expression of Krox-20, a master regulator of myelination, and that of myelin-specific proteins and lipids, suggesting that EPAC activation was insufficient to drive a full differentiating response. Interestingly, inhibition of EPAC activity resulted in a drastic impairment of SC differentiation and myelin formation but not Krox-20 expression, which indicates an independent mechanism of Krox-20 regulation in response to cAMP. In conclusion, our data supports the idea that the outcome of cAMP signaling in SCs depends on the particular set of effectors activated. Whereas the mitogenic action of cAMP relies exclusively on PKA activity, the differentiating action of cAMP requires a PKA-independent (non-canonical) cAMP-specific pathway that is partially transduced by EPAC.
Highlights
The ubiquitous second messenger cyclic adenosine monophosphate is a key regulator of metabolic activity, survival, proliferation and differentiation in a wide variety of cell types
Opposing roles of protein kinase A (PKA) and exchange protein activated by cAMP (EPAC) on the regulation of Schwann cells (SCs) proliferation and differentiation Our studies have shown that elevated intracellular cyclic adenosine monophosphate (cAMP) in SCs controls proliferation and differentiation via different signaling effectors
It is possible that an increase in the balance between EPAC and PKA switches the action of cAMP from a signal that enhances growth factor-induced proliferation into one that drives a program of differentiation into a myelinating phenotype
Summary
The ubiquitous second messenger cyclic adenosine monophosphate (cAMP) is a key regulator of metabolic activity, survival, proliferation and differentiation in a wide variety of cell types. An early event in the process of differentiation is the upregulation of the transcription factor Krox-20/Egr-2 [9], a master regulator of myelination which drives the expression of an array of myelin-related proteins and lipids These molecular changes occur in conjunction with the acquisition of a polarized and post-mitotic phenotype, the ensheathment of axons into one-to-one units and the wrapping of multiple layers of myelin membranes around higher caliber axons. Because of the strong pro-differentiating effects of cAMP observed in isolated SCs, it has long been suggested that a cAMP-dependent intracellular signal drives the process of myelination [1] This concept has been supported, at least in part, by the dependence on cAMP of the expression of crucial regulators of the myelinating phenotype, including the transcriptional enhancers Oct-6 [10,11], Krox-20 [12] and NFκB [13] as well as the transcriptional inhibitor c-Jun/AP1, a negative regulator of myelination [14]. The signal transduction mechanism underlying the action of cAMP on the differentiation of myelinating SCs remains mostly undefined
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