STRUCTURE AND FUNCTION OF MRG-FAMILY RECEPTORS

摘要 慢性疼痛影响了很大一部分美国人口，估计有10%-40%的成年人患有慢性疼痛。 阿片类药物和相关药物是治疗慢性疼痛最常用的处方药物之一， 虽然由于过量服药、便秘、上瘾和其他严重副作用而有相当大的风险。超过了 在过去的几十年里，我们对负责伤害性感受和抗伤害性治疗的神经回路的理解 已经揭示了几个分子靶点，它们是非阿片类药物缓解疼痛的潜在治疗靶点 药物治疗。其中包括与Mas相关的G蛋白偶联受体(MRGPR)。第一个MRGPR是 1986年被发现，从那时起，它们被发现包含一个约40个成员的GPCR家族， 高度定位于初级感觉神经节。MRGPR分为9个主要家族(即MRGPRA 通过MRGPRH和MRGPRX)，其中，MRGPRX受体家族被强调为一种 “灵长类专属”组富含人类感觉神经元。 我们最近发现MRGPRX2可能介导了肥大细胞依赖的超敏反应 由处方类阿片类药物和相关药物引起。我们还与合作者一起报告说， MRGPRX4基因多态性调节非洲人对薄荷醇香烟的偏好 血统。阿片类药物和其他药物与MRGPR受体相互作用的机制(S)尚不清楚 在这里，我们将通过对这些神秘受体的结构生物学研究来阐明它们的机制(S)。 使用这些结构，我们将发现和优化用于调节其功能的化学工具。这些 研究将有助于加深对MRGPR受体结构和功能的了解。这些发现可能会 加速寻找没有MRGPR介导的副作用并且可能起到 与MRGPR受体功能障碍相关的疾病的治疗。

ABSTRACT Chronic pain impacts a large proportion of the US population with estimates ranging from 10-40% of adults. Opioids and related medications are among the most frequently prescribed medications for treating chronic pain, albeit with considerable risks due to overdose, constipation, addiction and other serious side-effects. Over the past decades our understanding of the neural circuitry responsible for nociception and anti-nociceptive therapies has revealed several molecular targets that are potential therapeutic targets for non-opioid pain relieving medication. Among these are the Mas-related G protein coupled receptors (MRGPRs). The first MRGPR was discovered in 1986 and since then they have been found to encompass an ~40-member family of GPCRs that are highly localized to primary sensory ganglia. MRGPRs are divided into 9 major families (viz. MRGPRA through MRGPRH and MRGPRX) and, of these, the MRGPRX-family of receptors has been highlighted as a ‘primate-exclusive’ group enriched in human sensory neurons. We have recently shown that MRGPRX2 likely mediates the mast-cell dependent hypersensitivity responses caused by prescription opioids and related medications. We have also with collaborators reported that a polymorphism in MRGPRX4 mediates the preference for mentholated cigarettes among individuals with African ancestry. The mechanism(s) by which opioids and other drugs interact with MRGPR-receptors is unknown and here we will elucidate their mechanism(s) by structural biological investigation of these enigmatic receptors. Using these structures we will discover and optimize chemical tools with which to modulate their function. These studies will lead to an enhanced understanding of MRGPR-receptor structure and function. The findings may accelerate the search for medications devoid of MRGPR-mediated side effects and which may function as therapies for diseases linked to MRGPR-receptor dysfunction.