ANTIPSYCHOTICS AND RECEPTOR DESENSITIZATION MACHINERY

描述：（改编自申请人摘要） 蛋白偶联受体激酶（GRKs）参与同源 G蛋白偶联受体（GPCR）的脱敏。率 GPCRs的脱敏程度对药物浓度敏感， 细胞中的抑制蛋白和GRKS。反过来，逮捕和/或 GRKs可以通过GPCR的活性来调节。典型的抗精神病药物是 D2多巴胺受体的有效拮抗剂，而非典型药物相互作用 几个GPCR。几种GPCR的可塑性与精神分裂症有关 病理学和抗精神病药物的作用。[2019 - 02 - 15][2019 - 02 - 02][2019 - 02 - 02][2019 - 02 - 02] 抗精神病药物治疗引起的浓度的变化， 特定的抑制蛋白和/或GRK，从而修饰 在这些区域中通过GPCR进行信号转导。对这一假设的探索 是临床相关的，因为有益作用的分子机制 抗精神病药物的使用仍然是难以捉摸的。非典型的作用机制 抗精神病药对阴性症状的疗效更高， 认知缺陷是特别令人感兴趣的。具体目标旨在 检验这一假设包括确定抑制蛋白的库， GRK蛋白在纹状体和核内特定亚型输出神经元中的表达 大脑区域是抗精神病药物的主要目标。的 第二个具体目标侧重于比较急性和 典型抗精神病药物氟哌啶醇与非典型药物亚慢性治疗 氯氮平对抑制蛋白和GRK mRNA和蛋白表达的影响 与精神分裂症病理学和抗精神病药物作用有关的脑区。 第三个具体目标是确定是否在arrestin和 GRK表达与药物诱导的迟发性运动障碍的发生有关 氟哌啶醇长期治疗。神经元受体运输的可塑性 抗精神病药物治疗产生的系统可能会导致 浓度的特定GPCR，并最终，长期调节 神经元对内源性刺激和外源性药物的反应。具体 因此，抑制蛋白/GRK表达中的修饰可能是治疗糖尿病所必需的。 抗精神病药物的有益或副作用。我们预计 通过审查《公约》各主要组成部分的反应所获得的资料， 抗精神病药物的受体贩运机制将有助于靶向 设计具有改善的临床特征的药物。

DESCRIPTION: (Adapted from applicant's abstract) Arrestins and G protein-coupled receptor kinases (GRKs) participate in homologous desensitization of hundreds of G protein-coupled receptors (GPCRs). The rate and extent of desensitization of GPCRs is sensitive to the concentration of arrestins and GRKS in the cells. In its turn, the amount of arrestins and/or GRKs can be modulated by activity of GPCRs. Typical antipsychotic drugs are potent antagonists of the D2 dopamine receptor, whereas atypical drugs interact with several GPCRs. Plasticity of several GPCRs is implicated in schizophrenia pathology and actions of antipsychotic drugs. The a[[;ocamts hypothesize that treatment with antipsychotics induces alterations in the concentration of specific arrestins and/or GRKs in selected brain regions, thereby modifying signal transduction via GPCRs in these regions. Exploration of this hypothesis is clinically relevant because molecular mechanisms of the beneficial actions of antipsychotic drugs remain elusive. Mechanism of action of atypical antipsychotics with their higher efficacy against negative symptoms and cognitive deficits is of particular interest. The specific aims designed to test this hypothesis include determination of the repertoire of arrestin and GRK proteins in specific subtypes of output neurons in the striatum and nucleus accumbens, the brain regions that are prime targets of antipsychotics. The second specific aim focuses on comparison of the effects of acute and subchronic treatment with typical antipsychotic haloperidol and atypical drug clozapine on the expression of arrestin and GRK mRNAs and proteins in various brain areas implicated in schizophrenia pathology and action of antipsychotics. The third specific aim is to determine whether alterations in the arrestin and GRK expression are associated with development of tardive dyskinesia induced by chronic treatment with haloperidol. Plasticity of neuronal receptor trafficking system produced by antipsychotic treatment may lead to changes in the concentrations of specific GPCRs and, ultimately, to long-term modulations of neuronal responses to endogenous stimuli and exogenous drugs. Specific modifications in the arrestin/GRK expression may thus be essential for the beneficial or side effects of antipsychotic drugs. We expect that the information gained by examining the response of the key components of the receptor trafficking machinery to antipsychotics will be helpful for targeted design of drugs with improved clinical profile.