STRUCTURE AND FUNCTION OF MRG-FAMILY RECEPTORS

Document text

Principal Investigator: Bryan L. Roth
Organization: UNIV OF NORTH CAROLINA CHAPEL HILL
Fiscal Year: 2024
Award: $563,447
Funding agency: National Institute on Drug Abuse

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.

Terms: <21+ years old><Acceleration><Adrenergic Receptor><Adrenoceptors><Adult><Adult Human><Afferent Neurons><Affinity><African ancestry><African descent><Agonist><Allergy><Biochemical><Biological><Bioluminescence><Cell Communication and Signaling><Cell Signaling><Chemicals><Cigarette><Communities><Complex><Constipation><Coupling><Cryo-electron Microscopy><Cryoelectron Microscopy><Disease><Disorder><Docking><Dopamine><Drug Interactions><Drug Prescribing><Drug Prescriptions><Drugs><Dysfunction><Electron Cryomicroscopy><Epinephrine Receptors><Family><Family member><Functional disorder><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G-Protein-Coupled Receptors><G-Proteins><GPCR><GTP-Binding Proteins><GTP-Regulatory Proteins><Genetic Polymorphism><Genetics-Mutagenesis><Guanine Nucleotide Coupling Protein><Guanine Nucleotide Regulatory Proteins><Human><Hydroxytyramine><Hypersensitivity><Individual><Intracellular Communication and Signaling><Investigation><Itching><Libraries><Ligands><Link><Marrow Mast Cell><Mediating><Medication><Melatonin><Modern Man><Molecular><Molecular Target><Mutagenesis><Mutagenesis Molecular Biology><Nociception><Nociceptive Impulse><Nociceptive Stimulus><Opiate Receptors><Opiates><Opioid><Opioid Receptor><Overdose><Pain><Painful><Peptides><Pharmaceutical Preparations><Physiopathology><Population><Primates><Primates Mammals><Pruritic Disorder><Pruritis><Pruritus><Receptor Protein><Reporting><Research Resources><Resources><Risk><Sensory Ganglia><Sensory Neurons><Signal Transduction><Signal Transduction Systems><Signaling><Site-Directed Mutagenesis><Site-Specific Mutagenesis><Stimulus><Structure><Targeted DNA Modification><Targeted Modification><Testing><Therapeutic><Tissue Basophils><abused drug><abused drugs><addiction><addictive disorder><adenoreceptor><adulthood><antagonism><antagonist><antinociception><antinociceptive><biologic><biological signal transduction><chronic pain><chronic pain control><chronic pain intervention><chronic pain management><chronic pain therapy><chronic pain treatment><cryo-EM><cryoEM><cryogenic electron microscopy><drug abused><drug of abuse><drug/agent><drugs abused><drugs of abuse><itch sensation><licit opioid><mast cell><mastocyte><medication prescription><meter><neural circuit><neural circuitry><neurocircuitry><nociceptive><non-narcotic analgesic><non-opiate analgesic><non-opioid><non-opioid analgesic><non-opioid therapeutics><nonnarcotic analgesics><nonopiate analgesic><nonopioid><nonopioid analgesics><opiate medication><opioid medication><pain relief><pathophysiology><polymorphism><preference><prescribed medication><prescribed opiate><prescribed opioid><prescription opiate><prescription opioid><receptor><relieve pain><response><side effect><small molecule><synaptic circuit><synaptic circuitry><therapeutic target><tool><treat chronic pain><virtual library>