AKAP MODULATES TRPV1 PHOSPHORYLATION AND SENSITIZATION

AKAP 调节 TRPV1 磷酸化和致敏

• 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
• 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

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 Although pain disorders carry a large financial burden to society and the health care system, this is superseded by an incalculable loss in quality of life due to persistent peripheral pain.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)：神经元可塑性是一种普遍存在于记忆、运动和疼痛等多种功能中的普遍特征。因此，对可塑性机制的基础研究有可能对具有很高医学和科学影响的关键问题做出深刻贡献，特别是在外周疼痛的研究中。虽然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，这一点被生活质量的不可估量的损失所取代。在这个应用中，我们通过关注初级传入神经元水平上的活动依赖性变化来解决这个问题，这些变化发生在各种类型的损伤中，包括慢性损伤、神经病理性损伤和炎症性损伤。外周可塑性，即存在于外周传入终末的蛋白质的修饰/调制，突出了从正常的神经元信号通路到持续疼痛状态的高敏感性、伤害性转导的转变。最近，对伤害性信号的研究包括对受体通道的检测以及控制受体通道活动的生物化学和细胞调控机制。TRPV1家族的瞬时受体电位(Trp)受体通道是研究外周痛觉的主要成员，因为它已经得到了广泛的研究，并且表达在传递疼痛刺激(伤害性感受器)的非髓鞘C型神经元的子集上。TRPV1的翻译后修饰对损伤的反应，包括磷酸化，显著改变通道的活性，从而影响系统的可塑性。最近，我们已经证明了某些TRPV1的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的特征是仅介导蛋白激酶A(PKA)对底物的磷酸化，但最近的证据表明，AKAP还与PKC结合并指导其信号通路。在这个应用中，我们建议检验最初的假设，即AKAP组织TRPV1的翻译后磷酸化。为了实现这一点，我们将首先评估AKAP150与蛋白激酶C(PKC)结合的变化是否导致TRPV1磷酸化的变化和TRPV1通道活性的敏化。其次，我们将评估PKC的受体激活是否需要AKAP150改变TRPV1的磷酸化和敏化TRPV1通道的活性。第三，我们将在体内确定AKAP150是否通过PKA和PKC调节TRPV1的活性。我们的假设的验证将刺激未来的努力，以调查如何在临床相关的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RELEVACNE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。虽然疼痛障碍给社会和医疗保健系统带来了巨大的经济负担，但由于持续的疼痛，这被生活质量的不可估量的损失所取代。在这个应用中，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，以激励产生将抑制疼痛的新药。