DARPP-32 is a robust integrator of dopamine and glutamate signals.
DARPP-32 is a robust integrator of dopamine and glutamate signals.
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DOI：
10.1371/journal.pcbi.0020176
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发表时间：
2006-12-22
影响因子：
4.3
通讯作者：
Le Novère N
中科院分区：
文献类型：
--
作者：
Fernandez E;Schiappa R;Girault JA;Le Novère N
纹状体中神经递质和神经调质信号的整合在基底神经节的功能和功能障碍中起着中心作用。DARPP-32是GABA能中型多刺神经元中这种整合的关键因素，特别是响应多巴胺和谷氨酸。当被cAMP依赖性蛋白激酶（PKA）磷酸化时，DARPP-32抑制蛋白磷酸酶-1（PP 1），而当被细胞周期蛋白依赖性激酶5（CDK 5）磷酸化时，它抑制PKA。DARPP-32也受酪蛋白激酶和几种蛋白磷酸酶调节。这些复杂且错综复杂的法规使得对DARPP-32动态行为的简单预测几乎不可能。我们使用DARPP-32磷酸化调节的详细定量模型来提高我们对其功能的理解。这些模型包括DARPP-32的三个最佳特征磷酸化位点的所有组合，激酶和磷酸酶对其的调节，以及cAMP和Ca 2+信号对这些酶的调节。动态模拟使我们能够观察cAMP和Ca 2+信号之间的时间关系。我们证实了钙对蛋白磷酸酶-2A（PP 2A）的调节可以解释谷氨酸受体激活后观察到的Three 75磷酸化的减少。DARPP-32不仅仅是PP 1抑制和PKA抑制状态之间的转换。敏感性分析表明，CDK 5活性是一个主要的调节反应，如前所述。相反，在这些条件下，PKA或钙对PP 2A的调节强度对DARPP-32的PP 1抑制功能几乎没有影响。模拟表明DARPP-32不仅是一个强大的信号积分器，而且其响应还取决于cAMP和钙信号之间的延迟，影响对后者的响应。该积分不依赖于DARPP-32的浓度，而对PP 1的绝对影响呈线性变化。计算机模拟突变体显示Ser 137磷酸化影响多巴胺和谷氨酸之间的延迟的影响，并且Ser 137中的组成性磷酸化以准不可逆的开关转化DARPP-32。这项工作是第一次尝试更好地了解cAMP和Ca 2+调节DARPP-32之间的复杂相互作用。逐步列入其他组件应导致一个现实的模型，信号网络的功能纹状体神经元。纹状体的投射神经元是基底神经节的重要中继，参与运动、精神和行为功能。他们的重要性是强调他们参与各种功能障碍，如亨廷顿舞蹈症和精神分裂症，但也吸毒成瘾。对这些神经元的主要输入来自皮层神经元能末梢。多巴胺调节这种传递，提供了一种内部（享乐）状态的测量。在哺乳动物脑中，DARPP-32是一种蛋白磷酸酶抑制剂，已被鉴定为多巴胺和谷氨酸信号传导的主要靶点。作者提出了一个详细的定量模型的调节DARPP-32磷酸化和去磷酸化的两个信号。动态模拟表明，DARPP-32的功能取决于两个信号之间的延迟，因此该蛋白质不仅测量信号之间的强度，还测量信号之间的一致性。该测量对许多参数不敏感，无论是动力学常数还是浓度，使其成为一个强大的积分器。这表明，在基底神经节中的信号整合的正确理解，除了神经元的电生理特性的信号通路需要定量描述。
Integration of neurotransmitter and neuromodulator signals in the striatum plays a central role in the functions and dysfunctions of the basal ganglia. DARPP-32 is a key actor of this integration in the GABAergic medium-size spiny neurons, in particular in response to dopamine and glutamate. When phosphorylated by cAMP-dependent protein kinase (PKA), DARPP-32 inhibits protein phosphatase-1 (PP1), whereas when phosphorylated by cyclin-dependent kinase 5 (CDK5) it inhibits PKA. DARPP-32 is also regulated by casein kinases and by several protein phosphatases. These complex and intricate regulations make simple predictions of DARPP-32 dynamic behaviour virtually impossible. We used detailed quantitative modelling of the regulation of DARPP-32 phosphorylation to improve our understanding of its function. The models included all the combinations of the three best-characterized phosphorylation sites of DARPP-32, their regulation by kinases and phosphatases, and the regulation of those enzymes by cAMP and Ca2+ signals. Dynamic simulations allowed us to observe the temporal relationships between cAMP and Ca2+ signals. We confirmed that the proposed regulation of protein phosphatase-2A (PP2A) by calcium can account for the observed decrease of Threonine 75 phosphorylation upon glutamate receptor activation. DARPP-32 is not simply a switch between PP1-inhibiting and PKA-inhibiting states. Sensitivity analysis showed that CDK5 activity is a major regulator of the response, as previously suggested. Conversely, the strength of the regulation of PP2A by PKA or by calcium had little effect on the PP1-inhibiting function of DARPP-32 in these conditions. The simulations showed that DARPP-32 is not only a robust signal integrator, but that its response also depends on the delay between cAMP and calcium signals affecting the response to the latter. This integration did not depend on the concentration of DARPP-32, while the absolute effect on PP1 varied linearly. In silico mutants showed that Ser137 phosphorylation affects the influence of the delay between dopamine and glutamate, and that constitutive phosphorylation in Ser137 transforms DARPP-32 in a quasi-irreversible switch. This work is a first attempt to better understand the complex interactions between cAMP and Ca2+ regulation of DARPP-32. Progressive inclusion of additional components should lead to a realistic model of signalling networks underlying the function of striatal neurons. Projecting neurons of the striatum are a crucial relay of the basal ganglia, involved in motor, psychomotor, and behavioural functions. Their importance is emphasised by their involvement in various dysfunctions, such as Huntington chorea and schizophrenia, but also drug addiction. The main inputs to those neurons come from cortical glutamatergic terminals. Dopamine modulates this transmission, providing a measure of the internal (hedonic) state. In mammal brain, DARPP-32, a protein phosphatase inhibitor, has been identified as a major target for both dopamine and glutamate signalling. The authors present a detailed quantitative model of the regulation of DARPP-32 phosphorylation and dephosphorylation by both signals. Dynamic simulations show that the function of DARPP-32 depends on the delay between the two signals, and therefore the protein not only measures the intensity, but also the coincidence, between signals. This measurement is insensitive to many parameters, whether kinetic constants or concentrations, making it a robust integrator. This shows that a proper understanding of signal integration in the basal ganglia requires quantitative descriptions of the signalling pathways in addition to the neuronal electrophysiological properties.
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影响因子：
4.8
作者：
GRAVES, PR;ROACH, PJ
通讯作者：
ROACH, PJ
影响因子：
56.9
作者：
Fienberg, AA;Hiroi, N;Greengard, P
通讯作者：
Greengard, P
影响因子：
4.1
作者：
Briggs, GE;Haldane, JBS
通讯作者：
Haldane, JBS
影响因子：
--
作者：
Greengard, P;Nairn, AC;Nishi, A
通讯作者：
Nishi, A
DOI：
10.1073/pnas.0308265100
发表时间：
2004-02-17
影响因子：
11.1
作者：
Angeli, D;Ferrell, JE;Sontag, ED
通讯作者：
Sontag, ED