A Molecular Method to Selectively Record Activation of Dopamine Receptor Subtypes

神经元通过分泌称为神经递质的化学信号相互交流。的 从一个神经元分泌的神经递质与其他细胞膜上的特定受体结合 并在这些细胞中引发一系列反应。多巴胺是一种神经递质， 各种各样的生物过程，包括认知和情感，动机和奖励， 运动和某些激素的释放。多巴胺系统的不平衡 与精神分裂症、双相情感障碍、注意力缺陷多动等多种疾病有关 疾病、图雷特综合征、成瘾、帕金森病和高血压。哺乳动物 基因组编码五种不同的多巴胺受体，可以分为两类， 它们的细胞信号传导和序列同源性。人们认为各种类型的受体介导 不同的生物功能，并涉及不同的疾病。两类多巴胺 受体也可以被区分，但这种区分不是绝对的。 此外，要区分细胞内受体之间的差异要困难得多。 同一个班级。一种特定的药物通常作用于多种受体，产生不必要的副作用。因此，在本发明中， 对各种多巴胺受体具有高度特异性的药物是成功治疗的关键 一种涉及特定多巴胺受体类型的疾病，副作用最小。由于许多 神经元表达多种类型的多巴胺受体，目前还不可能将其影响归因于 一种特定的药物与一种特定的受体结合。临床上，这种知识的差距转化为无法 来预测和解决特定药物的副作用。 在这里，我们提出了一种新的分子方法，选择性地记录激活的特定 多巴胺受体亚型。由于我们的系统具有极强的选择性， 用于明确确定在特定神经元中哪种受体亚型被激活， 对特定药物的反应。这一过程与其他种类的多巴胺无关 神经元中的受体。我们将产生的动物模型将使发展和 测试副作用更少的特定药物。此外，我们的技术可以用来识别 在人类疾病如精神分裂症的小鼠模型中， 和帕金森病，提供线索的机制，潜在的进展， 这些疾病。最后，目前无法监测特定受体亚型的激活， 也适用于其他受体家族。由于我们的系统是模块化的，它可以很容易地适应 研究其他受体。一种选择性监测动物体内特异性受体激活的方法， 因此，该模型将对生物医学研究界的一个非常广泛的部分产生重大影响。

Neurons communicate with one another by secreting chemical signals called neurotransmitters. The neurotransmitters secreted from one neuron bind specific receptors on the membranes of other cells and elicit a cascade of responses in these cells. Dopamine is a neurotransmitter that regulates a diverse array of biological processes including cognition and emotion, motivation and reward, locomotion, and the release of certain hormones. Imbalances in the dopamine system have been implicated in disorders as diverse as schizophrenia, bipolar disorder, attention deficit hyperactivity disorder, Tourette's syndrome, addiction, Parkinson's disease, and hypertension. The mammalian genome encodes five different receptors for dopamine that can be grouped into two classes based on their cellular signaling and sequence homology. The various types of receptors are thought to mediate different biological functions and are implicated in different disorders. The two classes of dopamine receptors can also be distinguished pharmacologically, but this discrimination is not absolute. Furthermore, it is much more difficult to distinguish pharmacologically between receptors within the same class. A given drug often acts on multiple receptors, producing unwanted side effects. Thus, having highly specific drugs for the various dopamine receptors is critical for the successful treatment of a disorder that involves a particular dopamine receptor type with minimal side effects. Since many neurons express multiple types of dopamine receptors, it is currently impossible to attribute the effects of a particular drug to a specific receptor. Clinically, this gap of knowledge translates into an inability to predict and address the side effects of a given drug. Here we present a novel molecular method to selectively record activation of a particular dopamine receptor subtype in the murine brain. Since our system is extremely selective, it can be used to unequivocally determine which receptor subtype has been activated in a particular neuron in response to a given drug. This is accomplished regardless of the presence of other kinds of dopamine receptors in this neuron. The animal models that we will generate will enable the development and testing of specific drugs with fewer side effects. Moreover, our technology can be used to identify changes that occur in particular circuits in mouse models for human diseases such as schizophrenia and Parkinson's disease, providing clues regarding the mechanisms underlying the progression of these diseases. Finally, the current inability to monitor the activation of a particular receptor subtype also applies to other families of receptors. Since our system is modular, it can be readily adapted to study other receptors. A method to selectively monitor activation of specific receptors in an animal model will thus have a major impact on a very broad segment of the biomedical research community.