双稳态MAP激酶活性：维持晚期长时程增强的可能机制
Bistable MAP Kinase Activity: A Plausible Mechanism Contributing to Maintenance of Late Long-Term Potentiation
摘要：
MAP激酶（MAPK）活性的双稳态已被认为有助于几个细胞过程，包括分化和长时程突触增强。最近的一个模型（48）预测了由于MAPK途径中激酶和磷酸酶的相互作用而导致的双稳态，而没有MAPK对早期反应的反馈。使用这种模型和适合神经元的酶浓度，我们模拟了MAPK的活性，但双稳态只存在于一个相对狭窄的范围内的Raf，第一途径激酶的活性。分子数量的随机波动消除了小分子数量的双稳性，例如预期在树突棘的体积中。然而，正反馈回路已经假定从MAPK到Raf激活。一个提出的环，其中MAPK直接激活Raf被纳入模型。我们发现，这样的反馈大大提高了稳定状态的MAPK活性的随机波动和参数变化的鲁棒性。双稳态是强大的分子数量合理的树突棘体积。MAPK活性的上限状态对MEK活化的抑制具有抗性> 1小时，表明抑制剂实验不足以排除持续MAPK活性在LTP维持中的作用。这些模拟表明，持续的MAPK活性和随之而来的上调翻译可能有助于LTP的维护和长期记忆。使用荧光MAPK底物的实验可以进一步验证这一假设。
英文摘要：
Bistability of MAP kinase (MAPK) activity has been suggested to contribute to several cellular processes, including differentiation and long-term synaptic potentiation. A recent model (48) predicts bistability due to interactions of the kinases and phosphatases in the MAPK pathway, without feedback from MAPK to earlier reactions. Using this model and enzyme concentrations appropriate for neurons, we simulated bistable MAPK activity, but bistability only was present within a relatively narrow range of activity of Raf, the first pathway kinase. Stochastic fluctuations in molecule numbers eliminated bistability for small molecule numbers, such as are expected in the volume of a dendritic spine. However, positive feedback loops have been posited from MAPK up to Raf activation. One proposed loop in which MAPK directly activates Raf was incorporated into the model. We found that such feedback greatly enhanced the robustness of both stable states of MAPK activity to stochastic fluctuations and to parameter variations. Bistability was robust for molecule numbers plausible for a dendritic spine volume. The upper state of MAPK activity was resistant to inhibition of MEK activation for > 1 h, suggesting inhibitor experiments have not sufficed to rule out a role for persistent MAPK activity in LTP maintenance. These simulations suggest that persistent MAPK activity and consequent upregulation of translation may contribute to LTP maintenance and to long-term memory. Experiments using a fluorescent MAPK substrate may further test this hypothesis.
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