ANTIPSYCHOTICS AND RECEPTOR DESENSITIZATION MACHINERY

描述：(改编自申请人摘要)逮捕和G 蛋白偶联受体激酶(GRKs)参与同源 数百种G蛋白偶联受体(GPCRs)的脱敏。利率 GPCRs的脱敏程度对浓度敏感。 牢房里有阻滞剂和GRK。反过来，逮捕的数量和/或 GRKs可以被GPCRs的活性所调节。典型的抗精神病药物有 D2多巴胺受体的有效拮抗剂，而非典型药物相互作用 有几个GPCR。几种GPCR的可塑性与精神分裂症有关 抗精神病药物的病理学和作用。A[[；]假设 抗精神病药物治疗可引起血浆中 特定的抑制素和/或GRK在选定的大脑区域，从而改变 在这些区域通过GPCRs进行信号转导。对这一假说的探索 在临床上是相关的，因为有益作用的分子机制 抗精神病药物的种类仍然难以捉摸。非典型肺炎的作用机制 抗精神病药物对阴性症状和 认知缺陷尤其令人感兴趣。具体目标旨在 检验这一假设包括确定arrestin和arrestin的曲目 纹状体和核内特定亚型输出神经元中的GRK蛋白 伏隔核，是抗精神病药物的主要靶点。这个 第二个具体目标是比较急性和非传染性疾病的影响。 典型抗精神病药物氟哌啶醇与非典型药物的亚慢性治疗 氯氮平对不同组织中Arrestin和GRK基因及蛋白表达的影响 与精神分裂症病理和抗精神病药物作用有关的脑区。 第三个具体目标是确定Arrestin和Arrestin的变化是否 GRK的表达与迟发性运动障碍的发生有关 长期使用氟哌啶醇治疗。神经元受体转运的可塑性 抗精神病药物治疗产生的系统可能导致 特定GPCRs的浓度，并最终对 神经元对内源性刺激和外源性药物的反应。特定的 因此，arrestin/grk表达中的修饰可能对 抗精神病药物的有益或副作用。我们预计， 通过检查关键组成部分的反应而获得的信息 抗精神病药物的受体转运机制将有助于靶向 改善临床特征的药物设计。

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.