A Molecular Method to Selectively Record Activation of Dopamine Receptor Subtypes

选择性记录多巴胺受体亚型激活的分子方法

• 批准号: 8240088
• 负责人: Gilad Barnea
• 金额: $ 44.3万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8240088
• 关键词: Address; Adverse effects; Animal Model; Attention deficit hyperactivity disorder; Binding; Biological Process; Biomedical Research; Bipolar Disorder; Brain; Cells; Chemicals; Cognition; Communities; Development; Discrimination; Disease; Disease Progression; Dopamine; Dopamine Agonists; Dopamine Receptor; Emotions; Family; Gilles de la Tourette syndrome; Hormones; Hypertension; Knowledge; Locomotion; Mediating; Membrane; Methods; Molecular; Monitor; Motivation; Mus; Neurons; Neurotransmitters; Parkinson Disease; Peptide Signal Sequences; Pharmaceutical Preparations; Rewards; Schizophrenia; Sequence Homology; Signal Transduction; System; Technology; Testing; Translating; addiction; base; dopamine system; human disease; mammalian genome; mouse model; novel; receptor; response

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.

神经元通过分泌称为神经递质的化学信号相互交流。这 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，可调节 各种生物过程，包括认知和情感、动机和奖励， 运动和某些激素的释放。多巴胺系统失衡 与精神分裂症、双向情感障碍、注意力缺陷多动症等多种疾病有关 紊乱、抽动秽语综合征、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，可根据以下因素分为两类： 它们的细胞信号传导和序列同源性。各种类型的受体被认为可以介导 不同的生物学功能并与不同的疾病有关。两类多巴胺 受体也可以在药理学上进行区分，但这种区分并不是绝对的。 此外，从药理学角度区分受体内的受体要困难得多。 同一个班级。某种药物通常作用于多个受体，产生不良副作用。因此， 针对各种多巴胺受体的高度特异性药物对于成功治疗至关重要 涉及特定多巴胺受体类型且副作用最小的疾病。由于许多 神经元表达多种类型的多巴胺受体，目前无法归因其影响 特定药物作用于特定受体。在临床上，这种知识差距转化为无能 预测和解决给定药物的副作用。 在这里，我们提出了一种新颖的分子方法来选择性记录特定的激活 小鼠大脑中的多巴胺受体亚型。由于我们的系统具有极高的选择性，因此可以 用于明确确定特定神经元中哪种受体亚型已被激活 对给定药物的反应。无论是否存在其他种类的多巴胺，都会实现这一点 该神经元中的受体。我们将生成的动物模型将使开发和 测试副作用较少的特定药物。此外，我们的技术可用于识别 精神分裂症等人类疾病小鼠模型中特定电路发生的变化 和帕金森病，提供有关疾病进展机制的线索 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，因此可以轻松适应 研究其他受体。一种选择性监测动物特定受体激活的方法 因此，该模型将对生物医学研究界的广泛领域产生重大影响。

项目成果

Transsynaptic Mapping of Second-Order Taste Neurons in Flies by trans-Tango.

• DOI: 10.1016/j.neuron.2017.10.011
• 发表时间: 2017-11-15
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Talay M;Richman EB;Snell NJ;Hartmann GG;Fisher JD;Sorkaç A;Santoyo JF;Chou-Freed C;Nair N;Johnson M;Szymanski JR;Barnea G
• 通讯作者: Barnea G

A critical period defined by axon-targeting mechanisms in the murine olfactory bulb.

• DOI: 10.1126/science.1248806
• 发表时间: 2014-04-11
• 期刊: Science (New York, N.Y.)
• 作者: Tsai L;Barnea G
• 通讯作者: Barnea G