AKAP MODULATES TRPV1 PHOSPHORYLATION AND SENSITIZATION

AKAP 调节 TRPV1 磷酸化和致敏

基本信息

批准号：
8049940
负责人：
NATHANIEL Aaron JESKE
金额：
$ 5万
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/8049940
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 Although pain disorders carry a large financial burden to society and the health care system, this is superseded by an incalculable loss in quality of life due to persistent peripheral pain.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）：神经元可塑性是在记忆，运动和疼痛等功能中普遍存在的一般特征。因此，对可塑性机制的基本研究有可能为高度医学和科学影响的关键问题做出深远的贡献，尤其是在外围疼痛的研究中。尽管疼痛障碍给社会和医疗保健系统带来了巨大的经济负担，但由于持续的外围疼痛，生活质量损失不可估量，这取代了这一点。在此应用程序中，我们通过重点关注对各种损伤（包括慢性，神经性和炎症）的主要传入神经元水平上的活动依赖性变化来解决这个问题。外围塑性，外围传入末端的蛋白质的修饰/调节，突出了从正常的，神经元信号通路向持续性，疼痛状态的过敏性，伤害感受性传感器的过渡。最近，对伤害性信号传导的研究包括对受体通道的检查以及控制受体通道活性的调节性生化和细胞机制。瞬时受体电位（TRP）受体通道的TRPV1家族是研究周围疼痛感知研究的主要成员，因为它已经进行了广泛的检查，并以非层状的，C-Type神经元的子集表示，这些神经元会传递痛苦的刺激（Nocptors）。 TRPV1响应损伤的转化后修饰，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，我们证明了某些TRPV1磷酸化事件在功能上取决于脚手架蛋白A-激酶锚定蛋白（AKAP）。最初，AKAP的特征是仅介导蛋白激酶A（PKA）的磷酸化，尽管最近的证据表明AKAP也与PKC相关并指示其信号传导途径。在此应用程序中，我们建议测试AKAP组织TRPV1的转化后磷酸化的主要假设。为此，我们将首先评估AKAP150与蛋白激酶C（PKC）的变化是否导致TRPV1磷酸化和TRPV1通道活性的敏化的改变。其次，我们将评估PKC的受体激活是否需要AKAP150改变TRPV1磷酸化和TRPV1通道活性的敏化。第三，我们将确定AKAP150是否通过体内PKA和PKC调节TRPV1活动。对我们的假设的验证将刺激未来的努力，以研究如何通过临床相关的情况选择性控制PKA对AKAP组织的TRPV1磷酸化的修饰，以缓解周围疼痛。公共卫生相关的神经元可塑性机制的基础研究有可能在疼痛研究中为高医学和科学影响的关键问题做出深远的贡献。尽管疼痛障碍给社会和医疗保健系统带来了巨大的财务负担，但由于持续的疼痛，生活质量损失不可估量。在此应用中，我们通过确定脚手架蛋白AKAP在调节周围疼痛感应神经元的敏化方面的作用来解决此问题，以激发会抑制疼痛的新药的产生。