MONaKA -modulator of normal and neuropathological synaptic transmission

MONaKA - 正常和神经病理性突触传递的调节剂

• 批准号: 7760176
• 负责人: Tanya S. Ferguson
• 金额: $ 13.17万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7760176
• 关键词: ATP phosphohydrolase; Accounting; Affect; Affinity; Astrocytes; Binding; Binding Sites; Biochemical; Biological Assay; Brain; Catalytic Domain; Cell membrane; Cessation of life; Chronic; Co-Immunoprecipitations; Coupling; Data; Dependence; Development; Diagnosis; Disease; Electrophysiology (science); Epilepsy; Epileptogenesis; Equilibrium; Event; Excision; Fire - disasters; Foundations; Glutamate Transporter; Glutamates; Grant; Hippocampus (Brain); Human; Hyperactive behavior; In Vitro; Laboratories; Lead; Modeling; Molecular; Mutagenesis; Mutation; Na(+)-K(+)-Exchanging ATPase; Neuraxis; Neurons; Operative Surgical Procedures; Pennsylvania; Pharmacotherapy; Physiological; Pilocarpine; Pilot Projects; Prosencephalon; Proteins; Publications; Research Personnel; Risk; Role; Rosa; Seizures; Single Seizures; Sodium; Synapses; Synaptic Transmission; Techniques; Testing; Time; United States; Universities; Xenopus oocyte; extracellular; in vivo; neurotoxic; novel; prevent; protein expression; protein phosphatase inhibitor-2; public health relevance; research study; response; uptake; voltage

DESCRIPTION (provided by applicant): Modulating the activity of neurons in the brain is critical for normal synaptic transmission. In certain disease states, hyperactivity of neurons can lead to neuronal death. The novel protein that is the subject of this proposal is MONaKA (Modulator of Na,K-ATPase). The Na,K-ATPase is a critical protein for reestablishing the electrochemical gradient of neurons. Pharmacological blockade of the Na,K-ATPase can lead to neuronal death. MONaKA was first discovered as a modulator of the plasma membrane Na,K-ATPase. MONaKA binds to the ¿ subunit of the Na,K-ATPase and via this interaction, decreases the function of the a subunit. This is a unique discovery because most modulators of the Na,K-ATPase bind to the a subunit. Recently, I discovered that MONaKA binds to and modulates the Na+-dependent glutamate transporter, GLT-1. GLT-1 is primarily found on astrocytes and accounts for greater than 90% of synaptic glutamate removal in the mammalian forebrain. Maintaining extracellular levels of glutamate below neurotoxic levels is important for preventing neuronal death. Thus, the fact that MONaKA is able to bind and modulate this critical glutamate transporter is a novel and exciting discovery. Interestingly, GLT-1 also binds to the ¿ subunit of the Na,K- ATPase. This grant will explore MONaKA's modulation of GLT-1 and the ¿ subunit using electrophysiological techniques, as well as molecular mutagenesis to disrupt binding of all three proteins. The combined results from this proposal will determine the modulatory role of MONaKA on GLT-1 and Na,K-ATPase. These experiments will establish the foundation for exploring the in vivo role of MONaKA in normal and neuropathological synaptic transmission. PUBLIC HEALTH RELEVANCE: MONaKA (Modulator of Na,K-ATPase) is a novel protein that may modulate synaptic transmission in the central nervous system (CNS). It binds to and modulates two proteins important for neuronal activity, a glial glutamate transporter and the Na,K-ATPase. Because the CNS is a delicate balance of activity, studying a protein that modulates two critical proteins whose function are essential for neuronal activity is important in understanding and preventing neuronal death.

描述（适用提供）：调节大脑中神经元的活性对于正常突触传播至关重要。在某些疾病状态下，神经元的多动症会导致神经元死亡。该建议的新蛋白质是Monaka（Na，K-ATPase的调节剂）。 Na，K-ATPase是重建神经元电化学梯度的关键蛋白。 Na，K-ATPase的药理阻滞可导致神经元死亡。 Monaka首先被发现为质膜Na的调节剂K-ATPase。 Monaka与Na，K-ATPase的亚基结合，并通过这种相互作用降低A亚基的功能。这是一个独特的发现，因为Na，K-ATPase的大多数调节剂结合到A子单位。最近，我发现Monaka与Na+依赖性谷氨酸转运蛋白GLT-1结合并调节。 GLT-1主要在星形胶质细胞上发现，占哺乳动物前脑中突触谷氨酸的90％以上。在神经毒性水平以下保持细胞外谷氨酸水平对于预防神经元死亡很重要。这是一个新颖而令人兴奋的发现。有趣的是，GLT-1还与Na，K-ATPase的亚基结合。该赠款将使用电生理技术以及分子诱变来探索Monaka对GLT-1和子单位的调节，以破坏所有三种蛋白质的结合。该提案的综合结果将确定Monaka在GLT-1和Na，K-ATPase上的调节作用。这些实验将为探索莫纳卡在正常和神经病理突触传播中的体内作用而建立基础。公共卫生相关性：Monaka（Na，K-ATPase的调节剂）是一种新型蛋白质，可以调节中枢神经系统（CNS）中的突触传播。它与两种对神经元活性重要的蛋白质结合并调节，神经胶质谷氨酸转运蛋白和Na，K-ATPase。因为中枢神经系统是活性的专业平衡，因此研究一种调节两个关键蛋白质的蛋白质，其功能对于神经元活性至关重要，对于理解和预防神经元死亡至关重要。