MONaKA -modulator of normal and neuropathological synaptic transmission

描述（由申请人提供）：调节脑中神经元的活性对于正常突触传递至关重要。在某些疾病状态下，神经元的过度活跃可导致神经元死亡。作为该提案主题的新蛋白质是MONaKA（Na，K-ATP酶调节剂）。Na，K-ATP酶是重建神经元电化学梯度的关键蛋白。Na，K-ATP酶的药理学阻断可导致神经元死亡。MONaKA最初被发现是作为质膜Na，K-ATP酶的调节剂。MONaKA与Na，K-ATP酶的α亚基结合，并通过这种相互作用降低α亚基的功能。这是一个独特的发现，因为Na，K-ATP酶的大多数调节剂与α亚基结合。最近，我发现MONaKA结合并调节Na+依赖性谷氨酸转运蛋白GLT-1。GLT-1主要存在于星形胶质细胞上，并占哺乳动物前脑中突触谷氨酸清除的90%以上。维持细胞外谷氨酸水平低于神经毒性水平对于防止神经元死亡是重要的。因此，MONAKA能够结合和调节这种关键的谷氨酸转运蛋白的事实是一个新的和令人兴奋的发现。有趣的是，GLT-1也与Na，K-ATP酶的亚基结合.这项资助将探索MONAKA使用电生理技术对GLT-1和亚基的调节，以及分子诱变来破坏所有三种蛋白质的结合。该提议的综合结果将确定MONaKA对GLT-1和Na，K-ATP酶的调节作用。这些实验将为探索MONaKA在正常和神经病理性突触传递中的体内作用奠定基础。公共卫生相关性：MONaKA（Modulator of Na，K-ATP酶）是一种新型的调节中枢神经系统突触传递的蛋白质。它结合并调节两种对神经元活动重要的蛋白质，神经胶质谷氨酸转运蛋白和Na，K-ATP酶。因为CNS是活动的微妙平衡，所以研究调节两种关键蛋白质的蛋白质对于理解和预防神经元死亡是重要的，这两种关键蛋白质的功能对于神经元活动是必不可少的。

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.