Empirical and computational methods were combined to examine whether individual or dual-drug treatments can restore the deficit in long-term synaptic facilitation (LTF) of the Aplysia sensorimotor synapse observed in a cellular model of Coffin–Lowry syndrome (CLS). The model was produced by pharmacological inhibition of p90 ribosomal S6 kinase (RSK) activity. In this model, coapplication of an activator of the mitogen-activated protein kinase (MAPK) isoform ERK and an activator of protein kinase A (PKA) resulted in enhanced phosphorylation of RSK and enhanced LTF to a greater extent than either drug alone and also greater than their additive effects, which is termed synergism. The extent of synergism appeared to depend on another MAPK isoform, p38 MAPK. Inhibition of p38 MAPK facilitated serotonin (5-HT)-induced RSK phosphorylation, indicating that p38 MAPK inhibits activation of RSK. Inhibition of p38 MAPK combined with activation of PKA synergistically activated both ERK and RSK. Our results suggest that cellular models of disorders that affect synaptic plasticity and learning, such as CLS, may constitute a useful strategy to identify candidate drug combinations, and that combining computational models with empirical tests of model predictions can help explain synergism of drug combinations.

中文翻译：

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通过同时靶向 PKA 和 MAPK 通路来挽救 Coffin-Lowry 综合征模型中的缺陷突触可塑性

结合经验和计算方法来检查单独或双重药物治疗是否可以恢复在科芬-洛瑞综合征（CLS）细胞模型中观察到的海兔感觉运动突触的长期突触促进（LTF）缺陷。该模型是通过药理学抑制 p90 核糖体 S6 激酶 (RSK) 活性而产生的。在此模型中，共同应用丝裂原激活蛋白激酶 (MAPK) 同工型 ERK 激活剂和蛋白激酶 A (PKA) 激活剂导致 RSK 磷酸化增强和 LTF 增强，其程度比单独使用任一药物更大，并且也更大比它们的累加效应，这被称为协同作用。协同作用的程度似乎取决于另一种 MAPK 亚型，p38 MAPK。抑制 p38 MAPK 促进血清素 (5-HT) 诱导的 RSK 磷酸化，表明 p38 MAPK 抑制 RSK 的激活。p38 MAPK 的抑制与 PKA 的激活相结合，协同激活 ERK 和 RSK。我们的结果表明，影响突触可塑性和学习的疾病的细胞模型（例如 CLS）可能构成识别候选药物组合的有用策略，并且将计算模型与模型预测的经验测试相结合可以帮助解释药物组合的协同作用。