AKAP MODULATES TRPV1 PHOSPHORYLATION AND SENSITIZATION

AKAP 调节 TRPV1 磷酸化和敏化

• 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
• 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

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 Although pain disorders carry a large financial burden to society and the health care system, this is superseded by an incalculable loss in quality of life due to persistent peripheral pain.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一般特征。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，但由于持续的外周疼痛，生活质量的损失无法估量。在本申请中，我们通过关注初级传入神经元水平上的活性依赖性变化来解决这个问题，所述初级传入神经元响应于各种类型的损伤而发生，包括慢性损伤、神经性损伤和炎症性损伤。外周可塑性，修饰/调制的蛋白质存在于外周传入末梢，突出了从正常的，神经元信号传导通路的持续性，疼痛状态的超敏，伤害性换能器的过渡。近年来，对伤害性信号传导的研究已包括受体通道的检测以及控制受体通道活性的调节生化和细胞机制。瞬时受体电位（TRP）受体通道的TRPV 1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，并在传递疼痛刺激的无髓鞘C型神经元（伤害感受器）的子集上表达。TRPV 1响应于损伤的翻译后修饰，包括磷酸化，显著改变通道活性，从而影响系统的可塑性。最近，我们已经证明某些TRPV 1磷酸化事件在功能上依赖于支架蛋白A-激酶抑制蛋白（AKAP）。最初，AKAP被表征为仅介导底物的蛋白激酶A（PKA）磷酸化，尽管最近的证据表明AKAP也与PKC相关并指导其信号传导途径。在本申请中，我们提出检验AKAP组织TRPV 1的翻译后磷酸化的主要假设。为了实现这一点，我们将首先评估AKAP 150与蛋白激酶C（PKC）相关性的改变是否会导致TRPV 1磷酸化和TRPV 1通道活性敏化的改变。其次，我们将评估PKC的受体激活是否需要AKAP 150来改变TRPV 1的磷酸化和TRPV 1通道活性的敏化。第三，我们将确定AKAP 150是否通过PKA和PKC在体内调节TRPV 1活性。验证我们的假设将刺激未来的努力，以调查如何AKAP组织的PKA的TRPV 1磷酸化修饰可以选择性地控制在临床相关的情况下，以减轻外周疼痛。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刻贡献。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，但由于持续疼痛，生活质量的损失无法估量。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敏化中的作用来解决这个问题，以激发抑制疼痛的新药的产生。