Function of the adhesion-GPCR CIRL in nociception and pain resolution

粘附-GPCR CIRL 在伤害感受和疼痛缓解中的功能

• 批准号: 451489809
• 负责人: Professor Dr. Robert J. Kittel
• 金额: --
• 依托单位: Klinik und Poliklinik für Anästhesiologie
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/451489809?language=en
• 关键词: Function; adhesion; GPCR; CIRL; nociception

Adhesion-type G protein-coupled receptors (aGPCRs), a large molecule family with over 30 members in humans, operate in a vast range of physiological processes. Correspondingly, these receptors are associated with diverse human diseases, such as developmental disorders, defects of the nervous system, allergies, and cancer. Several aGPCRs have recently been linked to mechanosensitive functions suggesting that processing of mechanical stimuli may be a common feature of this receptor family, not only in classical mechanosensory structures. CIRL (ADGRL/Latrophilin, Lphn), one of the oldest members of the aGPCR family, modulates mechanosensory signal transduction bi-directionally in Drosophila. Whereas CIRL increases sensory responses to gentle touch and sound, the aGPCR decreases mechanical nociception in vivo by reducing intracellular cAMP concentrations. The present project will use optogenetics, electrophysiology and super-resolution light microscopy in Drosophila to elucidate the signaling mechanism of CIRL in nociceptors and to design neuropathy models to examine molecular pathways of pain resolution. To this end, a focused in vivo screen for nociception/pain resolution in bortezomib-induced polyneuropathy (BIPN) will include the aGPCR and candidate genes studied by other members of the CRU. In addition, we will investigate CIRL in the context of neuropathic pain resolution upon chronic constriction injury (CCI) and BPIN in rodents and in humans (work package 3). We propose that mammalian CIRL is involved in acute antinociception e.g. evoked by strong static or dynamic pressure. We further hypothesize that enhanced Cirl gene expression and protein function promote pain resolution by decreasing nociceptor cAMP levels via endogenous tonic activation independent of the full recovery of sensory function.

粘附型G蛋白偶联受体（aGPCR）是一个大分子家族，在人类中有超过30个成员，在广泛的生理过程中起作用。相应地，这些受体与多种人类疾病相关，例如发育障碍、神经系统缺陷、过敏和癌症。几个aGPCR最近已被链接到mechanosensitive功能，这表明机械刺激的处理可能是这个受体家族的一个共同特征，不仅在经典的mechanosensory结构。CIRL（ADGRL/Latrophilin，Lphn）是aGPCR家族最古老的成员之一，在果蝇中双向调节机械感觉信号转导。CIRL增加对轻柔触摸和声音的感觉反应，而aGPCR通过降低细胞内cAMP浓度来降低体内机械伤害感受。本项目将利用果蝇的光遗传学、电生理学和超分辨率光学显微镜来阐明CIRL在伤害感受器中的信号传导机制，并设计神经病模型来研究疼痛消退的分子途径。为此，针对硼替佐米诱导的多发性神经病（BIPN）中的伤害感受/疼痛缓解的集中体内筛选将包括由CRU的其他成员研究的aGPCR和候选基因。此外，我们将在啮齿动物和人类慢性压迫性损伤（CCI）和BPIN的神经性疼痛消退背景下研究CIRL（工作包3）。我们建议，哺乳动物CIRL参与急性抗伤害性感受，例如由强大的静态或动态压力引起的。我们进一步假设，增强的Cirl基因表达和蛋白质功能通过内源性紧张性激活降低伤害感受器cAMP水平来促进疼痛缓解，而不依赖于感觉功能的完全恢复。