The Regulation of Dopamine Neurotransmission by CDK5

描述（由申请人提供）：多巴胺神经传递对许多生理功能很重要，其失调导致许多神经系统疾病。以前，我们表明，神经元蛋白激酶Cdk 5通过将纹状体磷酸酶抑制剂DARPP-32转化为PKA抑制剂来调节多巴胺的功效。进一步的研究表明，通过药理学和转基因技术，Cdk 5可能调控纹状体中PKA的活性。在这里，我们提供的证据表明，Cdk 5调节PKA通过磷酸化PKA全酶RII 2亚基。此外，Cdk 5通过直接磷酸化磷酸二酯酶PDE 4 B或通过PKA和MAPK控制其调节来调节细胞内cAMP水平。我们建立了条件性Cdk 5敲除模型，发现成年小鼠中的敲除导致多巴胺信号的严重改变。我们建议进一步研究Cdk 5依赖的调节PKA信号通路在纹状体神经元中使用条件性敲除的方法。我们建议的生化机制，Cdk 5调节PKA在体外和完整的纹状体组织的特点。这些研究将为神经系统和神经精神疾病的新治疗方法的开发确定目标并提出策略。公共卫生相关性：由多巴胺神经传递中断引起的神经精神障碍包括精神分裂症、注意缺陷多动障碍和许多其他精神疾病。本研究的目的是描绘多巴胺神经传递调节的新机制，涉及神经元蛋白激酶Cdk 5，以便可以开发新的药物治疗这些疾病。

DESCRIPTION (provided by applicant): Dopamine neurotransmission is important for many physiological functions and its dysregulation contributes to numerous neurological disorders. Previously, we showed that the neuronal protein kinase Cdk5 modulates dopamine efficacy by converting the striatal phosphatase inhibitor DARPP-32 into a PKA inhibitor. Further studies of the regulation of dopamine signaling by Cdk5 using pharmacology and transgenic technology have revealed novel mechanisms by which Cdk5 is likely to govern PKA activity in the striatum. Here we provide evidence that Cdk5 regulates PKA through phosphorylation of the PKA holoenzyme RII2 subunit. Furthermore, Cdk5 regulates intracellular cAMP levels through direct phosphorylation the phosphodiesterase PDE4B or controlling its regulation by PKA and MAPK. We made conditional Cdk5 knockout models and found that knockout in adult mice results in severe alterations in dopamine signaling. We propose to further study Cdk5- dependent regulation of PKA signaling pathways in striatal neurons using a conditional knockout approach. We propose to characterize the biochemical mechanisms by which Cdk5 regulates PKA both in vitro and in intact striatal tissue. These studies will identify targets and suggest strategies for the development of new treatments for neurological and neuropsychiatric disorders. PUBLIC HEALTH RELEVANCE: Neuropsychiatric disorders that are caused by disruptions in dopamine neurotransmission include schizophrenia, attention deficit hyperactivity disorder, and numerous other mental illnesses. The goal of this research is to delineate new mechanisms by which dopamine neurotransmission is regulated involving the neuronal protein kinase Cdk5 so that new pharmacotherapeutic treatments for these disorders can be developed.