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

• 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
• 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

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.

总结： 疼痛影响着超过1亿的美国人，造成了毁灭性的影响，包括长期残疾， 精神健康共病和药物依赖以及巨大的经济负担。可用药物 慢性疼痛并不总是有效的，并且可能具有滥用倾向。迫切需要确定新的机制 用于治疗慢性疼痛。大量的证据支持杏仁核旁臂的可塑性的作用 神经元突触在疼痛慢性化中的作用，但其潜在机制尚未完全了解。我们有 最近证实谷氨酸δ 1受体（GluD 1; GRID 1基因：UniProt Q9 ULK 0）及其 突触发生结合伴侣小脑蛋白1（Cbln 1）在炎症和神经病理性 痛苦GluD 1是离子型谷氨酸受体家族的一员，但它是不寻常的，因为它缺乏典型的配体门控的谷氨酸受体。 离子通道活性，而是在突触形成/维持中起关键作用， GluD 1-Cbln 1-神经肽三联体。我们发现GluD 1-Cbln 1信号在疼痛状态下下调， AMPA受体亚单位表达增加。重要的是，我们发现将重组Cbln 1注射到中枢神经系统， 杏仁核使中枢神经系统GluD 1和AMPA受体表达的变化和神经元的过度兴奋正常化。 杏仁核，并减轻疼痛模型中的厌恶和情感行为。这些结果证明了GluD 1的作用。 cbln 1信号在疼痛诱导的可塑性中的作用。在另外的研究中，我们发现重组Cbln 1的镇痛作用 被D-丝氨酸抑制。已提出D-丝氨酸水平的增加主要是加剧伤害性行为 通过NMDA受体依赖性机制。然而，D-丝氨酸与GluD 1的配体结合结构域结合， 在受体中产生构象变化。最近的研究还报道了天然细胞中GluD 1的离子通道孔活性。 系统可能通过激活代谢型受体而被激活，并通过D-丝氨酸结合而被调节。的贡献 D-丝氨酸与GluD 1的结合以及GluD 1对疼痛机制的潜在离子通道孔活性尚不清楚。的目标 拟开展的研究是研究GluD 1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GluD 1的结合域和离子通道孔。提出了两个目标;目标1将 检测D-丝氨酸与GluD 1相互作用对重组Cbln 1镇痛作用的调节。目标2将检查 GluD 1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GluD 1可能导致慢性疼痛的新机制。预期的结果可能提供 通过靶向配体结合结构域或离子来开发慢性疼痛的新治疗方法的关键信息 GluD 1通道孔。