Agrin/alpha 3 Na,K-ATPase signaling at the neuromuscular junction

神经肌肉接头处的 Agrin/α 3 Na,K-ATP 酶信号转导

• 批准号: 8263408
• 负责人: MARTIN A SMITH
• 金额: $ 18.35万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8263408
• 关键词: Address; Affect; Agrin; Alternative Splicing; Amyotrophic Lateral Sclerosis; Animals; Axon; Binding; Botulinum Toxins; Brain; Breathing; Calcium; Caring; Cessation of life; Communication; Complex; Congenital Myasthenic Syndromes; Coupling; Deglutition; Dendrites; Development; Differentiation and Growth; Disease; Elements; Family; Gene Mutation; Glutamates; Grant; Growth; Growth Cones; Health; Health Benefit; Individual; Injury; Knock-out; Knockout Mice; LDL-Receptor Related Protein 1; Laboratories; Lambert-Eaton Myasthenic Syndrome; Life Expectancy; Link; Locomotion; Maintenance; Mediating; Membrane; Morbidity - disease rate; Motor; Motor Neurons; Movement; Muscle; Muscle Fibers; Muscle Weakness; Mutant Strains Mice; Myasthenia Gravis; Na(+)-K(+)-Exchanging ATPase; Nerve; Neuraxis; Neuromuscular Diseases; Neuromuscular Junction; Neurons; Pathway interactions; Peripheral; Phosphotransferases; Play; Presynaptic Terminals; Process; Productivity; Protein Isoforms; Protein Tyrosine Kinase; Proteins; Public Health; Pump; Rare Diseases; Regulation; Role; Schwann Cells; Second Messenger Systems; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Skeletal Muscle; Spinal Muscular Atrophy; Synapses; Synaptic Transmission; System; Testing; Toxin; Walking; agrin receptor; axon growth; cost; functional decline; neuromuscular; neuromuscular transmission; new therapeutic target; novel; novel therapeutics; postsynaptic; presynaptic; receptor; respiratory; response; second messenger; success; synaptic function; synaptogenesis; transmission process; treatment strategy

DESCRIPTION (provided by applicant): All coordinated movements such as locomotion, breathing, and swallowing, depend on the rapid transfer of information between motor neurons and the skeletal muscle fibers they innervate that takes place at a specialized contact called the neuromuscular junction. Disruption of this system by disease, as occurs in various myasthenic disorders, spinal muscular atrophy, and amyotrophic lateral sclerosis, toxins such as botulinum toxin, or traumatic injury, results in muscle weakness and even death. Thus, understanding the mechanisms responsible for the formation and maintenance of the neuromuscular junction has the potential for significant public health benefits by identifying new therapeutic targets for a wide range of disorders that impact the function of this important synapse. A major success in the field has been the elucidation of the role of a protein called agrin in mediating the motor neuron-induced differentiation of the postsynaptic apparatus formed by the muscle fiber. Agrin exerts its effects through a muscle fiber membrane receptor complex consisting of LRP4, a low-density lipoprotein receptor-related protein, and MuSK, a muscle-specific tyrosine kinase. Curiously, however, not all forms of agrin at the neuromuscular junction are competent to activate the LRP4/MuSK receptor and several studies have suggested these "inactive" agrin species play a role regulating growth and differentiation of motor axons and axon terminals. The receptor that might mediate these presynaptic effects is unknown but a good candidate is the a3 Na,K-ATPase (NKA), a neuron-specific isoform of the sodium-potassium pump that binds all forms of agrin. Agrin-dependent regulation of the a3 pump modulates excitability of central nervous system neurons, as well as the levels of cytoplasmic calcium and other second messengers implicated in regulating synaptic function, growth and maturation. The a3 NKA is also present on motor axon terminals, raising the possibility that the agrin/a3 NKA pathway plays a related role at the neuromuscular junction. To test this hypothesis we will examine the effect of knocking out the a3 NKA on development of the neuromuscular junction, the role of the a3 NKA in regulating growth of motor axons and dendrites, and the role of agrin/a3 NKA in modulating neuromuscular synaptic transmission. Previous studies of agrin function at the neuromuscular junction have focused on its interaction with the postsynaptic LRP4/MuSK receptor. This would be the first to examine the significance of an alternate agrin signaling pathway at this important synapse. Neuromuscular diseases such as the myasthenic disorders, spinal muscular atrophy, amyotrophic lateral sclerosis are characterized by profound muscle weakness linked to a decline in neuromuscular synaptic transmission. We believe the agrin/a3 NKA pathway will prove to be a novel therapeutic target that can be exploited for the treatment of these and related neuromuscular disorders. PUBLIC HEALTH RELEVANCE: The neuromuscular junction is the vital connection between the nerves and muscle fibers responsible for respiratory and voluntary movements. In many neuromuscular diseases, such as spinal muscular atrophy, myasthenia gravis and congenital myasthenic syndrome, the function of the neuromuscular junction is compromised resulting in profound muscle weakness and death. Here we examine a novel mechanism whereby agrin, a protein known for its role in directing the formation of the post-synaptic apparatus of the neuromuscular junction, influences growth and function of the pre-synaptic motor axon terminal. This novel signal pathway represents a new therapeutic target for the treatment of neuromuscular disease.

描述（由申请人提供）：所有协调的运动，如运动、呼吸和吞咽，都依赖于运动神经元和它们所支配的骨骼肌纤维之间的信息快速传递，这种信息传递发生在称为神经肌肉接点的特殊接触处。疾病破坏这个系统，如各种肌无力疾病、脊髓性肌萎缩症和肌萎缩性侧索硬化症、肉毒杆菌毒素等毒素或创伤性损伤，会导致肌肉无力甚至死亡。因此，了解神经肌肉连接形成和维持的机制，通过确定影响这一重要突触功能的各种疾病的新治疗靶点，具有潜在的重大公共卫生益处。该领域的一个主要成功是阐明了一种名为agrin的蛋白质在介导由肌肉纤维形成的突触后装置的运动神经元诱导分化中的作用。Agrin通过由LRP4（一种低密度脂蛋白受体相关蛋白）和MuSK（一种肌肉特异性酪氨酸激酶）组成的肌纤维膜受体复合物发挥作用。然而，奇怪的是，并非神经肌肉接点的所有形式的agrin都能激活LRP4/MuSK受体，一些研究表明，这些“不活跃”的agrin物种在调节运动轴突和轴突末端的生长和分化中发挥作用。可能介导这些突触前效应的受体尚不清楚，但一个很好的候选者是a3 Na， k - atp酶（NKA），一种结合所有形式的agrin的钠钾泵的神经元特异性异构体。a3泵的agrin依赖性调节中枢神经系统神经元的兴奋性，以及细胞质钙和其他参与调节突触功能、生长和成熟的第二信使的水平。a3 NKA也存在于运动轴突末端，这提出了agrin/a3 NKA通路在神经肌肉连接处起相关作用的可能性。为了验证这一假设，我们将研究敲除a3 NKA对神经肌肉连接发育的影响，a3 NKA在调节运动轴突和树突生长中的作用，以及agrin/a3 NKA在调节神经肌肉突触传递中的作用。先前对神经肌肉接点agrin功能的研究主要集中在其与突触后LRP4/MuSK受体的相互作用上。这将是第一次研究在这个重要的突触上另一种agrin信号通路的意义。神经肌肉疾病，如肌无力症、脊髓性肌萎缩症、肌萎缩侧索硬化症，其特征是与神经肌肉突触传递减少有关的严重肌肉无力。我们相信agrin/a3 NKA通路将被证明是一种新的治疗靶点，可以用于治疗这些和相关的神经肌肉疾病。