Ca Signaling Pathways and Receptors in Bipolar Disorder

双相情感障碍中的 Ca 信号通路和受体

• 批准号: 6834145
• 负责人: PETER M VASSILEV
• 金额: $ 21.26万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6834145
• 关键词: PCP receptor; antipsychotic agents; biological signal transduction; bipolar depression; calcium ion; electrophysiology; glutamate receptor; hippocampus; laboratory mouse; laboratory rat; lithium; mental disorder chemotherapy; neural transmission; prefrontal lobe /cortex; psychopharmacology; voltage /patch clamp

DESCRIPTION (provided by applicant): The causes of bipolar disorder (BPD) are not well understood and the therapeutic approaches are limited. The actions of Li+ and other anti-psychotic agents (ApsA) on membrane receptors and channels are related J to the modulation of intra- and extracellular Ca 2+ levels. We have cloned a Ca2+-sensing receptor (CaR) that plays a key role in the regulation of Ca/+ homeostasis and found that new specific CAR potentiators,/ calcimimetics, elicit beneficial effects on neuronal excitability and neurotransmission. The CaR is homologous to glutamate receptors (GR) and is functionally linked to both metabotropic GR (mGluR) and NMDA-type GR that are dysfunctional in psychosis. Based on our preliminary studies we suggest that the CaR potentiators can be applied for correction of these disturbances in BPD. We will also evaluate their synergistic actions with other ApsA including Li+. Li+ may exert its beneficial effects on BPD by modulating signal transduction pathways in the brain that are also regulated by CaR. One of the common side effects of Li is hypercalcemia that can be treated by CaR potentiators. We also found that these agents inhibit channels which likely play a role in rapid cycling BPD and that they can prevent the actions of phencyclidine (PCP) and other psychotomimetic agents on neuronal functions, thus displaying the characteristics of potent ApsA. We, therefore, hypothesize that the CaR potentiators can be used in combination with Li+ and other ApsA for treating BPD and for preventing complications associated with the side effects of Li+. We will characterize their effects on neuronal functions and will pursue the following specific aims: 1) To determine the role of the CaR and CaR-regulated signaling pathways as targets of Li+ action and the modulation by CaR potentiators and Li+ of channels involved in rapid cycling BPD. 2) To evaluate the application of the CAR potentiators as activators of NMDA channels, opposing the actions of PCP and other agents used for generating experimental models of psychotic states. 3) To document that there are positive functional links between CaR and mGluR2 by showing that the CaR potentiators can act via mGluR2 to prevent overstimulation by psychotomimetic agents and characterize the synergistic actions of CaR potentiators and other antipsychotic agents. These studies should provide new insights into the pathogenesis and treatment of bipolar disorder. In the long term, the application of CaR potentiators and their synergistic actions with other antipsychotic drugs could help introducing novel therapeutic strategies.

描述（由申请人提供）：双相情感障碍（BPD）的原因尚不清楚，并且治疗方法受到限制。 LI+和其他抗精神药物（APSA）对膜受体和通道的作用与j的调节和细胞外Ca 2+水平的调节有关。我们已经克隆了一个Ca2+传感器受体（CAR），该受体（CAR）在调节CA/+稳态中起着关键作用，发现新的特定汽车增强剂，/钙化，对神经元兴奋性和神经传递产生有益的有益作用。该汽车与谷氨酸受体（GR）是同源的，并且在精神病中功能失调的代谢性GR（MGLUR）和NMDA型GR在功能上都有联系。根据我们的初步研究，我们建议可以将汽车电位用于纠正BPD中的这些干扰。我们还将评估他们与包括Li+在内的其他APSA的协同行动。 Li+可以通过调节大脑中也受汽车调节的大脑信号转导途径来对BPD产生有益影响。 LI的常见副作用之一是高钙血症，可以由汽车电位治疗。我们还发现，这些试剂抑制了可能在快速循环BPD中发挥作用的通道，并且可以防止苯基二肽（PCP）和其他精神病剂对神经元功能的作用，从而显示出有效APSA的特征。因此，我们假设可以将汽车电位与LI+和其他APSA结合使用，以治疗BPD并防止与Li+的副作用相关的并发症。我们将表征它们对神经元功能的影响，并将追求以下特定目的：1）确定汽车和CAR调节的信号通路的作用，作为LI+动作的靶标，以及CAR Potentiators和Li+的调节，以及与快速循环BPD相关的通道的调节。 2）评估汽车电位器作为NMDA通道的激活因子的应用，与PCP和其他用于生成精神病态实验模型的药物的作用。 3）记录，通过表明汽车增强剂可以通过MGLUR2起作用，以防止精神映射剂过度刺激，并表征汽车增强剂和其他抗精神病药的协同作用，以证明汽车和MGLUR2之间存在积极的功能联系。这些研究应提供有关躁郁症的发病机理和治疗的新见解。从长远来看，汽车增强剂及其在其他抗精神病药中的协同作用的应用可能有助于引入新颖的治疗策略。