STRUCTURE AND FUNCTION OF MRG-FAMILY RECEPTORS

摘要 慢性疼痛影响大部分美国人口，估计范围为10-40%的成年人。 阿片类药物和相关药物是治疗慢性疼痛最常用的处方药， 尽管由于过量、便秘、成瘾和其他严重副作用而具有相当大的风险。来 过去几十年来，我们对负责伤害感受和抗伤害感受疗法的神经回路的理解 揭示了几个分子靶点，它们是非阿片类镇痛的潜在治疗靶点 药其中包括Mass相关的G蛋白偶联受体（MRGPR）。第一个MRGPR是 1986年发现，从那时起，人们发现它们包含一个约40个成员的GPCR家族， 主要集中在初级感觉神经节MRGPRs分为9个大家族（即MRGPRA 通过MRGPRH和MRGPRX），其中，MRGPRX受体家族已被强调为 “灵长类动物专属”组富含人类感觉神经元。 我们最近发现MRGPRX 2可能介导肥大细胞依赖性超敏反应 由处方阿片类药物和相关药物引起。我们还与合作者报告说， MRGPRX 4基因多态性介导了非洲人吸烟者对薄荷香烟的偏好。 祖先阿片类药物和其他药物与MRGPR受体相互作用的机制尚不清楚， 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。 使用这些结构，我们将发现和优化化学工具，以调节它们的功能。这些 研究将导致对MRGPR受体结构和功能的更好理解。这些发现可能 加速寻找没有MRGPR介导的副作用的药物， 治疗与MRGPR受体功能障碍相关的疾病。

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.