The Potassium Channel Slowpoke and the molecular mechanisms of Neuronal Homeost.

钾通道慢马和神经元稳态的分子机制。

• 批准号: 8687681
• 负责人: Bruno Marie
• 金额: $ 25.3万
• 依托单位: UNIVERSITY OF PUERTO RICO MED SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8687681
• 关键词: Affect; Alcohol dependence; Alzheimer' s Disease; Asorbicap; Binding; Biochemistry; Bypass; C-terminal; Calcium; Centers of Research Excellence; Co-Immunoprecipitations; Cognition; Complementary DNA; Confocal Microscopy; Disease; Drosophila genus; Ensure; Epilepsy; Failure; Financial compensation; Future; Generalized Epilepsy; Genetic; Goals; Heart; Homeostasis; Human; Image; Immunohistochemistry; Instruction; Ion Channel; Ions; Learning; Life; Link; Memory; Methods; Microscopy; Modification; Molecular; Molecular Genetics; Mutation; Nerve; Neurobiology; Neuromuscular Junction; Neuronal Plasticity; Neurons; P-Q type voltage-dependent calcium channel; Paroxysmal Dyskinesias; Pharmacology; Potassium Channel; Process; Property; Puerto Rico; Regulation; Research; Rest; Schizophrenia; Secure; Series; Signal Transduction; Signaling Molecule; Skeletal Muscle; Synapses; Synaptic plasticity; System; Tail; Testing; Therapeutic; Time; Transgenic Organisms; Universities; Up-Regulation; active control; addiction; autism spectrum disorder; base; dosage; flexibility; fly; mutant; neurotransmitter release; novel; postsynaptic; presynaptic; research study; scaffold; synaptic function; tool; two-photon

. PROJECT SUMMARY (See instructions): During our life time, homeostatic signaling systems secure the integrity of neuronal circuits while allowing some flexibility that will be the basis for processes of cognition, learning and memory. It is therefore not surprising that a series of neurobiological diseases (autism spectrum disorder, Alzheimer's disease and schizophrenia, among them) have been linked to alterations in homeostatic mechanisms. Despite the tremendous importance of understanding neuronal homeostasis and how homeostatic signaling systems interact with neuronal plasticity, we know close to nothing about the molecular mechanisms underlying synaptic homeostasis. We have recently discovered that the highly conserved BK-type K+ channel, slowpoke (slo) is essential to the homeostatic control of synaptic function. This study will define a new function for slo while characterizing a new molecular mechanism for the homeostatic stabilization of neuronal function. In human, mutation in slo has been implicated in generalized epilepsy and paroxysmal dyskinesia, slo is also known to control the active properties of neurons and skeletal muscles, to be essential to aspects of synaptic plasticity and alcohol addiction, and to bind to really important signaling molecules, including Ca2+ channels. This study will combine quintal analysis of different mutant backgrounds, pharmacology, molecular genetics, biochemistry and activity dependent Ca2+ imaging using two-photon microscopy to show that (1)- the modification of Ca2+ influx is the mechanism at the heart of homeostatic plasticity and that this mechanism depends on presynaptic slo. (2)- Slo conductance is not required to perform this function; the Slo C-terminus tail is sufficient to restore homeostasis, illustrating a new essential function for the regulatory Slo sequences. (3)- the Slo C-terminus tail interacts with the Ca2+ channel responsible for neurotransmitter release, CaV2.1 (Cae). This interaction is required for the upregulation of Cae during synaptic homeostasis.

。项目总结(见说明)： 在我们的生活中，动态平衡信号系统确保神经元电路的完整性，同时允许一些灵活性，这将是认知、学习和记忆过程的基础。因此，一系列神经生物学疾病(自闭症谱系障碍、阿尔茨海默病和精神分裂症等)与体内平衡机制的改变有关也就不足为奇了。尽管了解神经元稳态以及稳态信号系统如何与神经元可塑性相互作用是非常重要的，但我们对突触稳态背后的分子机制几乎一无所知。我们最近发现，高度保守的BK型K+通道Slow poke(SLO)对突触功能的动态平衡控制是必不可少的。这项研究将为SLO定义一个新的功能，同时表征一个新的神经元功能稳态稳定的分子机制。在人类中，SLO基因突变与全身性癫痫和阵发性运动障碍有关，SLO还被认为控制神经元和骨骼肌的活动特性，在突触可塑性和酒精成瘾方面是必不可少的，并与真正重要的信号分子结合，包括钙通道。本研究将结合对不同突变体背景的定量分析、药理学、分子遗传学、生物化学和双光子显微镜下的活性依赖的钙成像来证明：(1)钙离子内流的改变是稳态可塑性的核心机制，该机制依赖于突触前的sLO。(2)-Slo电导不需要执行这一功能；Slo C-末端的尾部足以恢复内稳态，说明了调节Slo序列的新的基本功能。(3)-Slo C末端尾巴与负责神经递质释放的钙通道CaV2.1(CAE)相互作用。这种相互作用是突触动态平衡期间CAE上调所必需的。