Modulation of GABAB receptor signaling

GABAB 受体信号传导的调节

• 批准号: 7928064
• 负责人: Stephen J Moss
• 金额: $ 58.02万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7928064
• 关键词: Address; Agonist; Animal Model; Anoxia; Automobile Driving; Baclofen; Biochemical; Brain; Cell Surface Receptors; Cell membrane; Cell surface; Coupling; Development; Disease; Endocytosis; Enzymes; Epilepsy; Exposure to; G-Protein-Coupled Receptors; Glutamate Receptor; Glutamates; Injury; Ischemia; Ischemic Brain Injury; Label; Laboratories; Lead; Link; Mediating; Mental Depression; Mental disorders; Metabolic; Metformin; N-Methyl-D-Aspartate Receptors; Neurologic; Neurons; Nociception; Pain; Patients; Phosphorylation; Phosphorylation Site; Play; Process; Protein Dephosphorylation; Protein Kinase; Protein Phosphatase 2A Regulatory Subunit PR53; Protein phosphatase; Receptor Activation; Receptor Signaling; Recovery; Recycling; Regulation; Role; Schizophrenia; Signal Transduction; Sorting - Cell Movement; Stroke; Testing; Trauma; Ubiquitination; addiction; excitotoxicity; insight; multicatalytic endopeptidase complex; neuronal survival; neurotransmission; novel therapeutics; protein kinase modulator; public health relevance; receptor; receptor function; research study; response; stressor; synaptic inhibition

DESCRIPTION (provided by applicant): Consistent with their roles in mediating neuronal inhibition, deficits in GABAB receptor function play significant roles in both neurological and psychiatric disorders that include ischemia, epilepsy, schizophrenia, addiction, and nociception. Given the clear significance of GABAB receptors in neurotransmission it is of fundamental importance to understand the endogenous mechanisms neurons use to regulate their activity under both control and pathological conditions. Previous studies from our laboratory have illustrated that GABAB receptors are phosphorylated by intimately-associated AMP-dependent protein kinase (AMPK) a process that enhances their activity, together with the strength of neuronal inhibition. AMPK is a key enzyme in regulating cellular levels of ATP and in mediating cellular responses to metabolic stressors that include ischemia and anoxia. Transient anoxia also increases AMPK-phosphorylation of GABAB receptors and neuronal survival after this trauma. In concordance with our results it is well documented that the GABAB agonist baclofen is neuroprotective in animal models of ischemia and is used "off-label" to aid recovery of patients after stroke. Given the established role of glutamate receptors in ischemia-induced excitotoxicity we have begun to explore the link between their activation and the regulation of AMPK-dependent phosphorylation of GABAB receptors. These preliminary studies have led us to formulate our central hypothesis: Prolonged exposure of neurons to glutamate via the activation of NMDA receptors inhibits AMPK-dependent phosphorylation of GABAB receptors. This deficit in phosphorylation enhances GABAB receptor ubiquitination, promoting their endocytosis from the plasma membrane and thereby reducing the efficacy of neuronal inhibition mediated by these critical GPCRS. Our experiments will focus on four distinct but related specific aims. 1. We will test the hypothesis that glutamate receptors modulate GABAB receptor phosphorylation and functional coupling. 2. We will test the hypothesis that glutamate receptor activation modulates the endocytosis and endocytic sorting of GABAB receptors. 3. We will test the hypothesis that inhibiting PP2A and proteasome activity regulates the effects of glutamate receptor activation on GABAB receptor cell surface stability. 4. We will test the hypothesis that blocking GABAB receptor dephosphorylation promotes neuronal survival after anoxia. PUBLIC HEALTH RELEVANCE: GABAB receptors are G-protein coupled receptors (GPCRs) that mediate slow and prolonged synaptic inhibition in the brain. Results of the experiments in this proposal will provide insights into the biochemical regulation of neuronal GABAB receptors under control and after anoxic insult similar to that occurring following ischemic brain injury. Given the critical roles that GABAB receptors play in regulating neuronal inhibition our studies will have the potential to make contributions to the development of novel therapeutics to enhance neuronal survival after ischemic injury and to alleviate other debilitating disorders including epilepsy, depression, schizophrenia, and pain.

描述（由申请人提供）：与其在介导神经元抑制中的作用一致，GABAB受体功能缺陷在神经和精神疾病中起重要作用，包括缺血、癫痫、精神分裂症、成瘾和伤害感受。鉴于GABAB受体在神经传递中的明确意义，理解神经元在控制和病理条件下用于调节其活性的内源性机制具有根本重要性。我们实验室之前的研究表明，GABAB受体被密切相关的AMP依赖性蛋白激酶（AMPK）磷酸化，这一过程增强了其活性，并增强了神经元抑制的强度。AMPK是调节细胞ATP水平和介导细胞对包括缺血和缺氧在内的代谢应激反应的关键酶。短暂缺氧也增加了GABAB受体的AMPK磷酸化和这种创伤后的神经元存活。与我们的结果一致，有充分的证据表明，GABAB激动剂巴氯芬在缺血的动物模型中具有神经保护作用，并被“标签外”使用以帮助中风后患者的恢复。鉴于谷氨酸受体在缺血诱导的兴奋性毒性中的既定作用，我们已经开始探索它们的激活和GABAB受体的AMPK依赖性磷酸化调节之间的联系。这些初步研究使我们形成了我们的中心假设：神经元通过激活NMDA受体而长时间暴露于谷氨酸，抑制GABAB受体的AMPK依赖性磷酸化。这种磷酸化缺陷增强GABAB受体泛素化，促进其从质膜的内吞作用，从而降低这些关键GPCRS介导的神经元抑制的功效。我们的实验将集中在四个不同但相关的具体目标上。1.我们将检验谷氨酸受体调节GABAB受体磷酸化和功能偶联的假设。2.我们将检验谷氨酸受体激活调节GABAB受体的内吞作用和内吞分选的假设。3.我们将检验抑制PP2A和蛋白酶体活性调节谷氨酸受体活化对GABAB受体细胞表面稳定性的影响的假设。4.我们将检验阻断GABAB受体去磷酸化促进缺氧后神经元存活的假设。公共卫生相关性：GABAB受体是G蛋白偶联受体（GPCR），介导大脑中缓慢和长期的突触抑制。在这个建议中的实验结果将提供深入了解神经元GABAB受体的生化调节下的控制和缺氧损伤后发生类似的缺血性脑损伤。鉴于GABAB受体在调节神经元抑制中发挥的关键作用，我们的研究将有可能为开发新的治疗方法做出贡献，以提高缺血性损伤后的神经元存活率，并减轻其他衰弱性疾病，包括癫痫，抑郁症，精神分裂症和疼痛。