AKAP MODULATES TRPV1 PHOSPHORYLATION AND SENSITIZATION

AKAP 调节 TRPV1 磷酸化和敏化

基本信息

批准号：
7643087
负责人：
NATHANIEL Aaron JESKE
金额：
$ 32.47万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7643087
关键词：
A kinase anchoring protein Address Affect Afferent Neurons Amino Acids Analgesics Attenuated Behavior Biochemical Bradykinin Bradykinin B2 Receptor Cell membrane Chemicals Chronic Clinical Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Dinoprostone Event Family Future Generations Glutamates Healthcare Systems Heating Homologous Gene Human Inflammatory Injury Investigation Measures Mediating Medical Memory Modeling Modification Molecular Movement Neuronal Plasticity Neurons Neuropathy Nociception Nociceptors Pain Pain Disorder Pathway interactions Perception Peripheral Persistent pain Pharmaceutical Preparations Phosphorylation Phosphotransferases Population Post-Translational Protein Processing Protein Kinase C Proteins Public Health Quality of life Rattus Receptor Activation Regulation Rodent Role Scaffolding Protein Signal Pathway Signal Transduction Skin Small Interfering RNA Societies Stimulus Structure of trigeminal ganglion System TRPV1 gene Testing Thermal Hyperalgesias Transducers Validation citrate carrier clinically relevant desensitization design fundamental research in vivo inhibitor/antagonist innovation insight knock-down member novel pain inhibition receptor research study response response to injury

项目摘要

DESCRIPTION (provided by applicant): Neuronal plasticity is a general feature prevalent among functions as diverse as memory, movement, and pain. Therefore, fundamental research into mechanisms of plasticity has the potential for profound contributions to key questions of high medical and scientific impact, especially in the study of peripheral pain. Although pain disorders carry a large financial burden to society and the health care system, this is superseded by an incalculable loss in quality of life due to persistent peripheral pain. In this application, we address this issue by focusing on activity-dependent changes at the level of the primary afferent neuron that occur in response to various types of injury, including chronic, neuropathic and inflammatory. Peripheral plasticity, the modification/ modulation of proteins present at peripheral afferent terminals, highlights the transition from normal, neuronal signaling pathways into hypersensitive, nociceptive transducers of persistent, painful states. Recently, the study of nociceptive signaling has included the examination of receptor-channels and the modulatory biochemical and cellular mechanisms that control receptor-channel activity. The TRPV1 family of Transient Receptor Potential (TRP) receptor-channels serves as a principal member for the study of peripheral pain perception, as it has been examined extensively and is expressed on a subset of non-myelinated, C-type neurons that transmit painful stimuli (nociceptors). Post- translational modifications of TRPV1 in response to injury, including phosphorylation, significantly alter channel activity, and thereby affect the plasticity of the system. Recently, we have demonstrated that certain TRPV1 phosphorylation events are functionally dependent upon the scaffolding protein A-Kinase Anchoring Protein (AKAP). Initially, AKAP was characterized as solely mediating Protein Kinase A (PKA) phosphorylation of substrates, although recent evidence indicates that AKAP also associates with PKC and directs its signaling pathway as well. In this application, we propose to test the primary hypothesis that AKAP organizes the post- translational phosphorylation of TRPV1. To accomplish this, we will first evaluate whether alterations in AKAP150 association with Protein Kinase C (PKC) leads to alterations in TRPV1 phosphorylation and sensitization of TRPV1 channel activity. Second, we will evaluate whether receptor-activation of PKC requires AKAP150 to alter TRPV1 phosphorylation and sensitization of TRPV1 channel activity. Thirdly, we will determine whether AKAP150 modulates TRPV1 activity via PKA and PKC in vivo. Validation of our hypothesis will stimulate future endeavors to investigate how AKAP-organized modifications of TRPV1 phosphorylation by PKA can be selectively controlled in clinically relevant situations to relieve peripheral pain. PUBLIC HEALTH RELEVACNE Fundamental research into mechanisms of neuronal plasticity has the potential for profound contributions to key questions of high medical and scientific impact in the study of pain. Although pain disorders carry a large financial burden to society and the health care system, this is superseded by an incalculable loss in quality of life due to persistent pain. In this application, we address this issue by determining the role of the scaffolding protein AKAP in modulating the sensitization of pain-sensing neurons in the periphery, to inspire the generation of new drugs that will inhibit pain.

描述（由申请人提供）：神经元可塑性是记忆、运动和疼痛等多种功能中普遍存在的普遍特征。因此，对可塑性机制的基础研究有可能对具有高度医学和科学影响的关键问题做出深远的贡献，特别是在外周疼痛的研究中。尽管疼痛疾病给社会和医疗保健系统带来了巨大的经济负担，但持续性周围疼痛导致的生活质量无法估量的损失所取代。在此应用中，我们通过关注初级传入神经元水平的活动依赖性变化来解决这个问题，这些变化是响应各种类型的损伤（包括慢性损伤、神经病理性损伤和炎症性损伤）而发生的。外周可塑性是对外周传入末梢存在的蛋白质的修饰/调节，强调从正常的神经元信号传导途径到持续、疼痛状态的超敏、伤害性传感器的转变。最近，伤害性信号传导的研究包括对受体通道以及控制受体通道活性的调节生化和细胞机制的检查。 TRPV1 瞬时受体电位 (TRP) 受体通道家族是外周疼痛感知研究的主要成员，因为它已被广泛研究并在传递疼痛的非髓鞘 C 型神经元子集上表达。刺激（伤害感受器）。 TRPV1 响应损伤的翻译后修饰（包括磷酸化）显着改变通道活性，从而影响系统的可塑性。最近，我们证明某些 TRPV1 磷酸化事件在功能上依赖于支架蛋白 A-激酶锚定蛋白 (AKAP)。最初，AKAP 被描述为仅介导蛋白激酶 A (PKA) 底物的磷酸化，尽管最近的证据表明 AKAP 也与 PKC 相关并指导其信号通路。在本申请中，我们建议测试 AKAP 组织 TRPV1 翻译后磷酸化的主要假设。为了实现这一目标，我们将首先评估 AKAP150 与蛋白激酶 C (PKC) 关联的改变是否会导致 TRPV1 磷酸化和 TRPV1 通道活性敏化的改变。其次，我们将评估 PKC 受体激活是否需要 AKAP150 来改变 TRPV1 磷酸化和 TRPV1 通道活性的敏化。第三，我们将确定AKAP150是否在体内通过PKA和PKC调节TRPV1活性。我们假设的验证将激发未来的努力，研究如何在临床相关情况下选择性地控制 AKAP 组织的 PKA 对 TRPV1 磷酸化的修饰，以缓解外周疼痛。公共卫生相关性对神经元可塑性机制的基础研究有可能对疼痛研究中具有高度医学和科学影响的关键问题做出深远贡献。尽管疼痛疾病给社会和医疗保健系统带来了巨大的经济负担，但持续疼痛导致的生活质量无法估量的损失所取代。在本申请中，我们通过确定支架蛋白 AKAP 在调节外周痛觉神经元的敏化中的作用来解决这个问题，以激发抑制疼痛的新药物的产生。