Control of βAR- and N-methyl-D-aspartate (NMDA) Receptor-Dependent cAMP Dynamics in Hippocampal Neurons.
Control of βAR- and N-methyl-D-aspartate (NMDA) Receptor-Dependent cAMP Dynamics in Hippocampal Neurons.
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DOI：
10.1371/journal.pcbi.1004735
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发表时间：
2016-02
影响因子：
4.3
通讯作者：
Blackwell KT
中科院分区：
文献类型：
--
作者：
Chay A;Zamparo I;Koschinski A;Zaccolo M;Blackwell KT
去甲肾上腺素是一种神经调节剂，可以激活β肾上腺素能受体(βAR)，促进学习和记忆，并在海马区诱导突触可塑性。Schaffer侧支CA1突触的几种形式的长时程增强(LTP)需要刺激β受体和N-甲基-D-天冬氨酸受体(NMDAR)。为了了解β受体和NMDAR信号通路之间相互作用的机制，我们将海马神经元培养中cAMP的FRET成像与CA1锥体神经元信号通路的空间力学模型相结合。以前的工作表明，在β受体激动剂异丙肾上腺素和细胞内钙存在的情况下，cAMP是协同产生的。相反，我们发现，当应用异丙肾上腺素比应用N-甲基-D-天冬氨酸早几分钟时，与单独使用N-甲基-D-天冬氨酸相比，cAMP对N-甲基-D-天冬氨酸的反应平均幅度减弱，这是典型的βAR促进的长时程增强实验。模型模拟表明，尽管cAMP、cAMP依赖的蛋白激酶(PKA)和4型磷酸二酯酶形成的负反馈环可能参与减弱cAMP对NMDA的反应，但这不足以解释实验观察的范围。相反，cAMP反应的减弱需要腺酰环化酶上游的机制。我们的模型表明，由于βARs的PKA磷酸化以及GI抑制1型腺酰环化酶而导致的Gs到Gi的转换可能是实验观察的基础。这表明，β-肾上腺素能受体的信号传递依赖于刺激的时间模式，这种转换可能代表了一种新的机制，可以招募参与突触可塑性和记忆的激酶。去甲肾上腺素是一种压力相关分子，当在海马体中释放时，它有助于学习和记忆。记忆的易化与突触可塑性的调节有关，但这种调节的机制尚不清楚。我们利用活细胞成像和计算建模的组合来发现去甲肾上腺素受体刺激如何与突触可塑性和记忆存储所需的其他分子相互作用，如钙。虽然先前的工作表明去甲肾上腺素受体和钙同时结合时协同作用增加细胞内第二信使，但我们的结果表明预先刺激去甲肾上腺素受体抑制细胞内第二信使的增加。我们的结果进一步证明，这种抑制可能是由去甲肾上腺素能受体转换信号通路引起的，从而招募了一组不同的记忆激酶。这种转换代表了一种新的机制来招募与突触可塑性和记忆有关的分子。
Norepinephrine, a neuromodulator that activates β-adrenergic receptors (βARs), facilitates learning and memory as well as the induction of synaptic plasticity in the hippocampus. Several forms of long-term potentiation (LTP) at the Schaffer collateral CA1 synapse require stimulation of both βARs and N-methyl-D-aspartate receptors (NMDARs). To understand the mechanisms mediating the interactions between βAR and NMDAR signaling pathways, we combined FRET imaging of cAMP in hippocampal neuron cultures with spatial mechanistic modeling of signaling pathways in the CA1 pyramidal neuron. Previous work implied that cAMP is synergistically produced in the presence of the βAR agonist isoproterenol and intracellular calcium. In contrast, we show that when application of isoproterenol precedes application of NMDA by several minutes, as is typical of βAR-facilitated LTP experiments, the average amplitude of the cAMP response to NMDA is attenuated compared with the response to NMDA alone. Models simulations suggest that, although the negative feedback loop formed by cAMP, cAMP-dependent protein kinase (PKA), and type 4 phosphodiesterase may be involved in attenuating the cAMP response to NMDA, it is insufficient to explain the range of experimental observations. Instead, attenuation of the cAMP response requires mechanisms upstream of adenylyl cyclase. Our model demonstrates that Gs-to-Gi switching due to PKA phosphorylation of βARs as well as Gi inhibition of type 1 adenylyl cyclase may underlie the experimental observations. This suggests that signaling by β-adrenergic receptors depends on temporal pattern of stimulation, and that switching may represent a novel mechanism for recruiting kinases involved in synaptic plasticity and memory. Noradrenaline is a stress related molecule that facilitates learning and memory when released in the hippocampus. The facilitation of memory is related to modulation of synaptic plasticity, but the mechanisms underlying this modulation are not well understood. We utilize a combination of live cell imaging and computational modeling to discover how noradrenergic receptor stimulation interacts with other molecules, such as calcium, required for synaptic plasticity and memory storage. Though prior work has shown that noradrenergic receptors and calcium interact synergistically to elevate intracellular second messengers when combined simultaneously, our results demonstrate that prior stimulation of noradrenergic receptors inhibits the elevation of intracellular second messengers. Our results further demonstrate that the inhibition may be caused by the noradrenergic receptor switching signaling pathways, thereby recruiting a different set of memory kinases. This switching represents a novel mechanism for recruiting molecules involved in synaptic plasticity and memory.