Sorbonne Université, CNRS, Biological Adaptation and Ageing, F-75005 Paris, France.
Science for Life Laboratory, School of Computer Science and Communication, KTH Royal Institute of Technology, Stockholm, 10044, Sweden.
J Cell Sci. 2018 Jul 27;131(14):jcs216556. doi: 10.1242/jcs.216556.
Although it is known that protein kinase A (PKA) in the nucleus regulates gene expression, the specificities of nuclear PKA signaling remain poorly understood. Here, we combined computational modeling and live-cell imaging of PKA-dependent phosphorylation in mouse brain slices to investigate how transient dopamine signals are translated into nuclear PKA activity in cortical pyramidal neurons and striatal medium spiny neurons. We observed that the nuclear PKA signal in striatal neurons featured an ultrasensitive responsiveness, associated with fast all-or-none responses, which is not consistent with the commonly accepted theory of a slow and passive diffusion of catalytic PKA in the nucleus. Our numerical model suggests that a positive feed-forward mechanism inhibiting nuclear phosphatase activity - possibly mediated by DARPP-32 (also known as PPP1R1B) - could be responsible for this non-linear pattern of nuclear PKA response, allowing for a better detection of the transient dopamine signals that are often associated with reward-mediated learning.
虽然已知核内蛋白激酶 A（PKA）可调节基因表达，但核内 PKA 信号的特异性仍知之甚少。在这里，我们结合计算建模和小鼠脑片上 PKA 依赖性磷酸化的活细胞成像，研究了短暂的多巴胺信号如何转化为皮质锥体神经元和纹状体中间神经元中的核 PKA 活性。我们观察到，纹状体神经元中的核 PKA 信号具有超敏反应性，与快速全有或全无反应相关，这与核内催化 PKA 缓慢和被动扩散的公认理论不一致。我们的数值模型表明，正向正反馈机制抑制核磷酸酶活性 - 可能由 DARPP-32（也称为 PPP1R1B）介导 - 可能是这种核 PKA 反应非线性模式的原因，从而可以更好地检测与奖励介导学习相关的短暂多巴胺信号。
