Structure-Function and Signaling of Glutamate Delta 1 in Pain Mechanism

疼痛机制中谷氨酸 Delta 1 的结构功能和信号传导

基本信息

批准号：
10688445
负责人：
Shashank Manohar Dravid
金额：
$ 40.43万
依托单位：
CREIGHTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-15 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10688445
关键词：
AMPA Receptors Affect Affective American Amygdaloid structure Analgesics Axosomatic Synapse Behavior Binding Brain Clinical Complex Crystallization D-Amino Acid Dehydrogenase Dependence Down-Regulation Drug Addiction Economic Burden Electrophysiology (science)Exhibits Family Genes Genetic Models Glutamate Receptor Glutamates Glycine Goals Incidence Injections Ion Channel Ion Channel Gating Knowledge Lateral Ligand Binding Domain Ligands Maintenance Mediating Mental Health Modeling Molecular Conformation Mus N-Methyl-D-Aspartate Receptors Neurons Nociception Outcome Pain Pain management Pathway interactions Persistent pain Pharmaceutical Preparations Play Recombinants Regulation Reporting Role Serine Signal Transduction Slice Specificity Structure Structure-Activity Relationship Synapses System Therapeutic Viral Vector abuse liability adeno-associated viral vector cell type chronic pain chronic pain management comorbidity disability gene product glutamatergic signaling inflammatory pain local drug delivery member mutant neglect neuronal excitability new therapeutic target novel novel therapeutic intervention overexpression pain behavior pain chronification pain model painful neuropathy parabrachial nucleus pharmacologic prevent receptor receptor expression side effect small molecule synaptogenesis tool

项目摘要

Summary: Pain affects more than 100 million Americans producing devastating effects including long-term disabilities, mental health comorbidities and drug dependence as well as enormous economic burden. Available medications for chronic pain are not always effective and may have abuse liability. There is an urgent need to identify novel mechanisms for the treatment of chronic pain. A large body of evidence supports a role of plasticity of parabrachio-amygdala glutamatergic synapses in chronification of pain, but the underlying mechanisms are not fully understood. We have recently demonstrated a critical role of glutamate delta 1 receptor (GluD1; gene GRID1: UniProt Q9ULK0) and its synaptogenic binding partner cerebellin 1 (Cbln1) at the parabrachio-amygdala synapses in inflammatory and neuropathic pain. GluD1 is a member of the ionotropic glutamate receptor family but is unusual because it lacks typical ligand-gated ion channel activity and instead plays a critical role in synapse formation/maintenance by forming a trans-synaptic GluD1-Cbln1-Neurexin triad. We found a downregulation of GluD1-Cbln1 signaling in pain states and a contrasting increase in AMPA receptor subunit expression. Importantly, we found that injection of recombinant Cbln1 into the central amygdala normalized the changes in GluD1 and AMPA receptor expression and neuronal hyperexcitability in the central amygdala and also mitigated averse and affective behaviors in pain models. These results demonstrate a role of GluD1- Cbln1 signaling in pain-induced plasticity. In additional studies we found that the analgesic effect of recombinant Cbln1 was inhibited by D-serine. An increase in D-serine levels has been proposed to exacerbate nocifensive behaviors primarily via a NMDA receptor-dependent mechanism. However, D-serine binds to the ligand binding domain of GluD1 and produces conformational changes in the receptor. Recent studies also report ion channel pore activity of GluD1 in native system potentially trigged by activation of metabotropic receptors and modulated by D-serine binding. The contribution of D-serine binding to GluD1 and potential ion channel pore activity of GluD1 to pain mechanisms is unknown. The goal of the proposed studies is to examine the structure-function relationship of GluD1 specifically probing the function of ligand binding domain and ion channel pore of GluD1 in amygdala pain mechanisms. Two aims are proposed; Aim 1 will examine the regulation of analgesic effect of recombinant Cbln1 by D-serine interaction with GluD1. Aim 2 will examine the ion channel function of GluD1 in relation to pain mechanism. This project is significant because it will identify a novel mechanism by which the enigmatic GluD1 may contribute to chronic pain. The expected outcomes may provide critical information to develop new therapeutic approaches for chronic pain by targeting the ligand binding domain or ion channel pore of GluD1.

概括：疼痛影响着超过 1 亿美国人，造成毁灭性影响，包括长期残疾、精神健康合并症和药物依赖以及巨大的经济负担。可用药物用于慢性疼痛并不总是有效，并且可能存在滥用倾向。迫切需要确定新机制用于治疗慢性疼痛。大量证据支持臂旁杏仁核可塑性的作用谷氨酸能突触在疼痛慢性化中的作用，但其潜在机制尚不完全清楚。我们有最近证明了谷氨酸 delta 1 受体（GluD1；基因 GRID1：UniProt Q9ULK0）的关键作用及其炎症和神经病变中腕旁杏仁核突触的突触结合伴侣小脑蛋白 1 (Cbln1) 疼痛。 GluD1 是离子型谷氨酸受体家族的成员，但很不寻常，因为它缺乏典型的配体门控离子通道活动，而是通过形成跨突触在突触形成/维持中发挥关键作用 GluD1-Cbln1-Neurexin 三联体。我们发现在疼痛状态下 GluD1-Cbln1 信号传导下调，而在疼痛状态下 GluD1-Cbln1 信号传导下调 AMPA 受体亚基表达增加。重要的是，我们发现将重组 Cbln1 注射到中枢杏仁核使中枢 GluD1 和 AMPA 受体表达以及神经元过度兴奋的变化正常化杏仁核，还减轻了疼痛模型中的厌恶和情感行为。这些结果证明了 GluD1- 的作用疼痛诱导的可塑性中的 Cbln1 信号传导。在其他研究中，我们发现重组 Cbln1 的镇痛作用被D-丝氨酸抑制。已提出增加 D-丝氨酸水平主要会加剧伤害行为通过 NMDA 受体依赖性机制。然而，D-丝氨酸与 GluD1 的配体结合域结合，使受体发生构象变化。最近的研究还报道了天然 GluD1 的离子通道孔活性该系统可能由代谢型受体的激活触发并由 D-丝氨酸结合调节。的贡献 D-丝氨酸与 GluD1 的结合以及 GluD1 的潜在离子通道孔活性对疼痛机制的影响尚不清楚。目标是拟议的研究是检查 GluD1 的结构-功能关系，特别是探测配体的功能杏仁核疼痛机制中 GluD1 的结合域和离子通道孔。提出了两个目标；目标1将检查重组 Cbln1 通过 D-丝氨酸与 GluD1 相互作用对镇痛作用的调节。目标 2 将检查 GluD1 的离子通道功能与疼痛机制的关系。该项目意义重大，因为它将确定一个神秘的 GluD1 可能导致慢性疼痛的新机制。预期结果可能会提供通过靶向配体结合域或离子来开发慢性疼痛新治疗方法的关键信息 GluD1 的通道孔。