Subunit dependent properties of kainate receptors

红藻氨酸受体的亚基依赖性特性

• 批准号: 8097586
• 负责人: JANET L FISHER
• 金额: $ 30.08万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8097586
• 关键词: Affect; Affinity; Agonist; Autistic Disorder; Binding; Brain; Cells; Cognitive; Data; Development; Disease; Electrophysiology (science); Epilepsy; Event; Exhibits; Frequencies; Gated Ion Channel; Generations; Glutamates; Goals; Health; Hippocampus (Brain); Huntington Disease; Immunohistochemistry; Kainic Acid Receptors; Kinetics; Lentivirus Vector; Light; Mediating; Modeling; Mutate; Neuraxis; Neurons; One-Step dentin bonding system; Physiological; Pilocarpine; Play; Polyamines; Process; Property; Proteins; Protons; RNA; Recombinants; Regulation; Relative (related person); Role; Schizophrenia; Seizures; Site; Site-Directed Mutagenesis; Slice; Status Epilepticus; Subfamily lentivirinae; Synapses; Synaptic Transmission; Temporal Lobe Epilepsy; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Time; Zinc; desensitization; design; kainate; kynurenate; mossy fiber; nervous system disorder; neuronal excitability; neurotransmission; novel; novel therapeutics; painful neuropathy; receptor; receptor function

DESCRIPTION (provided by applicant): Kainate receptors are glutamate-gated ion channels that mediate synaptic transmission and regulate cellular excitability in the central nervous system. They contribute to cognitive processing by participating in the generation of rhythmic oscillations of hippocampal neurons at behaviorally relevant frequencies. Kainate receptors have also been implicated in a number of neurological disorders including temporal lobe epilepsy, schizophrenia, autism, and neuropathic pain. Rational development of novel therapies targeting these receptors depends upon a better understanding of their function. Kainate receptors are tetrameric and comprised of low affinity GluR5-7 and high affinity KA1 and KA2 subunits. Functional properties of kainite receptors depend upon their subunit composition. In particular, KA2-containing kainate receptors play a distinctive role in neuronal excitation. Current at KA2-containing kainate receptors exhibits a higher conductance and slower decay than that at KA2-lacking kainate receptors. In addition, KA2-containing kainate receptors enhance intrinsic neuronal excitability through a noncanonical metabotropic action. Perhaps because of their importance in neuronal excitation, receptors containing the KA2 subunit exhibit significantly increased sensitivity to modulation by a variety of endogenous agents, including protons, polyamines and zinc. While recent studies have shed light on the roles of KA2-containing kainate receptors in physiological conditions, little is known about how the expression of kainate receptor subunits or the functional role of these receptors changes in disease. Kainate receptors have long been implicated in mechanisms underlying temporal lobe epilepsy. A better understanding of how the properties and regulation of kainate receptors change in temporal lobe epilepsy would provide valuable information in the design of novel therapies for this disease. This project will examine the role of the KA2 subunit in kainate receptors in physiological conditions and in epilepsy. Aim 1 will use recombinant receptors to define the functional contribution of KA2 subunits to kainate receptors. Aim 2 will use lentiviral vectors and pharmacological agents to determine the effect of changes in KA2 subunit expression on KAR-mediated neurotransmission. Aim 3 will use quantitative real time qRT-PCR and immunohistochemistry to determine the time course of changes in KAR subunit RNA and protein in the hippocampus during the development of epilepsy after pilocarpine-induced status epilepticus (SE). Hippocampal slice electrophysiology combined with pharmacological agents and lentiviral vectors will then define how SE-induced alterations in subunit expression change functional properties of kainate receptors at these same time points. PUBLIC HEALTH RELEVANCE: Kainate receptors are glutamate-gated ion channels that are critical for synaptic transmission and can contribute to neurological diseases, such as temporal lobe epilepsy, schizophrenia, autism, and neuropathic pain. The goals of this study are to examine subunit dependent properties of these receptors and the impact of changes in subunit composition on hippocampal function. A better understanding of kainate receptor properties is essential in the rational development of novel therapeutic agents targeted at these receptors.

描述（申请人提供）：盐酸盐受体是谷氨酸门控离子通道，介导中枢神经系统突触传递和调节细胞兴奋性。它们通过参与海马神经元在行为相关频率上的节律振荡的产生来促进认知加工。盐酸盐受体也与许多神经系统疾病有关，包括颞叶癫痫、精神分裂症、自闭症和神经性疼痛。针对这些受体的新疗法的合理开发取决于对其功能的更好理解。盐酸盐受体是四聚体，由低亲和力GluR5-7和高亲和力KA1和KA2亚基组成。kainite受体的功能特性取决于它们的亚基组成。特别是，含有ka2的盐酸盐受体在神经元兴奋中起着独特的作用。在含ka2的盐酸盐受体上，电流比在缺乏ka2的盐酸盐受体上表现出更高的电导和更慢的衰减。此外，含有ka2的盐酸盐受体通过非典型代谢作用增强神经元的内在兴奋性。也许是因为它们在神经元兴奋中的重要性，含有KA2亚基的受体对各种内源性药物（包括质子、多胺和锌）的调节表现出显著增加的敏感性。虽然最近的研究揭示了含ka2的盐酸盐受体在生理条件下的作用，但对盐酸盐受体亚基的表达或这些受体在疾病中的功能作用的变化知之甚少。盐酸盐受体长期参与颞叶癫痫的机制。更好地了解盐酸盐受体在颞叶癫痫中的特性和调控变化将为设计这种疾病的新疗法提供有价值的信息。本项目将研究KA2亚基在生理条件和癫痫中盐酸盐受体中的作用。目的1将使用重组受体来确定KA2亚基对盐酸盐受体的功能贡献。Aim 2将使用慢病毒载体和药理学试剂来确定KA2亚基表达变化对kar介导的神经传递的影响。Aim 3将使用定量实时qRT-PCR和免疫组织化学来确定匹罗卡品诱导癫痫持续状态（SE）后癫痫发展过程中海马KAR亚基RNA和蛋白质变化的时间过程。海马体切片电生理学结合药物和慢病毒载体将确定se诱导的亚基表达改变如何在这些时间点改变盐酸盐受体的功能特性。公共卫生相关性：盐酸盐受体是谷氨酸门控离子通道，对突触传递至关重要，可导致神经系统疾病，如颞叶癫痫、精神分裂症、自闭症和神经性疼痛。本研究的目的是研究这些受体的亚基依赖性特性以及亚基组成变化对海马功能的影响。更好地了解盐酸盐受体的性质对于合理开发针对这些受体的新型治疗剂至关重要。