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）的病因尚不清楚，治疗方法也有限。 Li+ 和其他抗精神病药物 (ApsA) 对膜受体和通道的作用与细胞内和细胞外 Ca 2+ 水平的调节有关。我们克隆了一种 Ca2+ 感应受体 (CaR)，它在 Ca2+ 稳态调节中发挥关键作用，并发现新的特异性 CAR 增强剂/拟钙剂可对神经元兴奋性和神经传递产生有益影响。 CaR 与谷氨酸受体 (GR) 同源，并且在功能上与代谢型 GR (mGluR) 和 NMDA 型 GR 相关，而后者在精神病中功能失调。根据我们的初步研究，我们建议 CaR 增强剂可用于纠正 BPD 中的这些干扰。我们还将评估它们与包括 Li+ 在内的其他 ApsA 的协同作用。 Li+ 可能通过调节大脑中也受 CaR 调节的信号转导途径来发挥对 BPD 的有益作用。 Li 的常见副作用之一是高钙血症，可以通过 CaR 增强剂治疗。我们还发现这些药物抑制可能在快速循环 BPD 中发挥作用的通道，并且它们可以阻止苯环己哌啶 (PCP) 和其他拟精神病药物对神经元功能的作用，从而显示出有效的 ApsA 的特征。因此，我们假设 CaR 增强剂可以与 Li+ 和其他 ApsA 联合使用，用于治疗 BPD 并预防与 Li+ 副作用相关的并发症。我们将描述它们对神经元功能的影响，并追求以下具体目标：1) 确定 CaR 和 CaR 调节信号通路作为 Li+ 作用靶标的作用以及 CaR 增效剂和 Li+ 对参与快速循环的通道的调节边缘性人格障碍。 2) 评估 CAR 增强剂作为 NMDA 通道激活剂的应用，反对 PCP 和其他用于生成精神病状态实验模型的药物的作用。 3）证明CaR和mGluR2之间存在积极的功能联系，表明CaR增强剂可以通过mGluR2发挥作用，以防止拟精神病药物的过度刺激，并表征CaR增强剂和其他抗精神病药物的协同作用。这些研究应该为双相情感障碍的发病机制和治疗提供新的见解。从长远来看，CaR 增强剂的应用及其与其他抗精神病药物的协同作用可能有助于引入新的治疗策略。