STRUCTURE AND FUNCTION OF MRG-FAMILY RECEPTORS

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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.