Influence of cAMP and protein kinase A on neurite length from spiral ganglion neurons.
Influence of cAMP and protein kinase A on neurite length from spiral ganglion neurons.
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DOI：
10.1016/j.heares.2011.11.010
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发表时间：
2012-01
期刊：
影响因子：
2.8
通讯作者：
Hansen, Marlan R.
中科院分区：
文献类型：
--
作者：
Xu, Ningyong;Engbers, Jonathan;Khaja, Sobia;Xu, Linjing;Clark, J. Jason;Hansen, Marlan R.
外周螺旋神经节神经元（SGN）纤维的再生是改善人工耳蜗植入结局和潜在地重新支配再生毛细胞的主要目标。环磷酸腺苷（cAMP）通过激活蛋白激酶A（PKA）和环磷酸腺苷直接激活的交换蛋白（Epac）来调节轴突生长和导向。在这里，我们探讨了cAMP信号对体外SGN神经突长度的影响。我们发现，cAMP类似物，cpt-cAMP，对神经突长度产生双相效应;在较低浓度下增加长度，在较高浓度下减少长度。这种双相反应发生在层粘连蛋白、纤连蛋白或腱生蛋白C上的培养物中，表明它不是底物依赖性的。cpt-cAMP还减少SGN神经突分支。Epac特异性激动剂8-pCPT-2 '-O-Me-cAMP不改变SGN神经突长度。组成型活性PKA亚型强烈抑制SGN神经突长度类似于较高水平的cAMP。慢性膜去极化激活SGN中的PKA，也抑制SGN神经突长度。然而，PKA的抑制未能拯救神经突长度在去极化文化意味着PKA的激活是不必要的慢性去极化抑制SGN神经突长度。组成型活性磷脂酰肌醇3-激酶的表达，而不是c-Jun N-末端激酶，在活化PKA的存在下，亚型部分拯救SGN神经突长度。总之，这些结果表明，cAMP/PKA的激活代表了一种潜在的策略，以提高SGN纤维伸长耳聋后，然而，这种疗法可能需要仔细滴定，以同时促进而不是抑制神经纤维再生。
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.
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