Influence of cAMP and protein kinase A on neurite length from spiral ganglion neurons

Abstract

Regrowth of peripheral spiral ganglion neuron (SGN) fibers is a primary objective in efforts to improve cochlear implant outcomes and to potentially reinnervate regenerated hair cells. Cyclic adenosine monophosphate (cAMP) regulates neurite growth and guidance via activation of protein kinase A (PKA) and Exchange Protein directly Activated by Cylic AMP (Epac). Here we explored the effects of cAMP signaling on SGN neurite length in vitro. We find that the cAMP analog, cpt-cAMP, exerts a biphasic effect on neurite length; increasing length at lower concentrations and reducing length at higher concentrations. This biphasic response occurs in cultures plated on laminin, fibronectin, or tenascin C suggesting that it is not substrate dependent. cpt-cAMP also reduces SGN neurite branching. The Epac-specific agonist, 8-pCPT-2’-O-Me-cAMP, does not alter SGN neurite length. Constitutively active PKA isoforms strongly inhibit SGN neurite length similar to higher levels of cAMP. Chronic membrane depolarization activates PKA in SGNs and also inhibits SGN neurite length. However, inhibition of PKA fails to rescue neurite length in depolarized cultures implying that activation of PKA is not necessary for the inhibition of SGN neurite length by chronic depolarization. Expression of constitutively active phosphatidylinositol 3-kinase, but not c-Jun N-terminal kinase, isoforms partially rescues SGN neurite length in the presence of activated PKA. Taken together, these results suggest that activation of cAMP/PKA represents a potential strategy to enhance SGN fiber elongation following deafness; however such therapies will likely require careful titration so as to simultaneously promote rather than inhibit nerve fiber regeneration.

Lipidic nanocapsule drug delivery: neuronal protection for cochlear implant optimization

“…They were able to show an increased length at lower concentrations and reduced length at higher concentrations. 43 On the other hand, in the present study, rolipram-loaded nanoparticles significantly elongated the neurites in 1:50 dilution when compared to the unloaded LNC in 1:50 dilution. One could speculate that this divergence is based on the rolipram and that this finding supports the hypothesis that rolipram positively affects neurite outgrowth.…”

Exchange Protein Directly Activated by cAMP (epac): A Multidomain cAMP Mediator in the Regulation of Diverse Biological Functions

“…Although few studies indicate that developmental and/or regenerative neuronal responses do not rely on Epac (Emery and Eiden, 2012;Xu et al, 2012), a growing list of recent studies point to a central function of Epac. Together with PKA, Epac regulates polarized responses of neuronal growth cone attraction and repulsion.…”

Role of protein kinase A in regulating mitochondrial function and neuronal development: implications to neurodegenerative diseases

“…Paradoxically, while a basal amount of PKA activity is required for promoting neurite outgrowth, high levels of PKA activity simplifies and shortens dendrites in neurons (Copf. 2014) (Xu, et al 2012). For instance, treating spiral ganglion neurons with a low concentration of cyclic AMP promotes the sprouting of dendrites while high concentrations of cAMP blunts dendrites and promotes apoptosis even in the absence of toxic insults (Xu, et al 2012).…”

“…2014) (Xu, et al 2012). For instance, treating spiral ganglion neurons with a low concentration of cyclic AMP promotes the sprouting of dendrites while high concentrations of cAMP blunts dendrites and promotes apoptosis even in the absence of toxic insults (Xu, et al 2012). Therefore, a proper balance of local PKA activity is critical for promoting optimal growth of dendritic arbors in developing neurons.…”