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

黏附型G蛋白偶联受体（agpcr）是一个大分子家族，在人体中有30多个成员，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有关，如发育障碍、神经系统缺陷、过敏和癌症。最近，一些agpcr与机械敏感功能有关，这表明机械刺激的处理可能是该受体家族的共同特征，而不仅仅是在经典的机械感觉结构中。CIRL （ADGRL/Latrophilin, Lphn）是aGPCR家族中最古老的成员之一，在果蝇中双向调节机械感觉信号转导。CIRL增加了对轻柔触摸和声音的感觉反应，而aGPCR通过降低细胞内cAMP浓度来减少体内的机械性伤害感受。本项目将利用光遗传学、电生理学和超分辨率光学显微镜在果蝇中阐明CIRL在伤害感受器中的信号传导机制，并设计神经病变模型来研究疼痛缓解的分子途径。为此，一项针对硼替佐米诱导的多神经病变（BIPN）的痛觉/疼痛缓解的集中体内筛选将包括aGPCR和CRU其他成员研究的候选基因。此外，我们将研究CIRL在啮齿动物和人类慢性收缩损伤（CCI）和BPIN神经性疼痛缓解的背景下（工作包3）。我们认为哺乳动物的CIRL参与了急性抗感觉反应，例如由强静态或动态压力引起的。我们进一步假设Cirl基因表达和蛋白功能的增强通过内源性强直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。

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.