title: The G protein-coupled receptor-transient receptor potential channel axis: molecular insights for targeting disorders of sensation and inflammation.
abstract: Sensory nerves are equipped with receptors and ion channels that allow them to detect and respond to diverse chemical, mechanical, and thermal stimuli. These sensory proteins include G protein-coupled receptors (GPCRs) and transient receptor potential (TRP) ion channels. A subclass of peptidergic sensory nerves express GPCRs and TRP channels that detect noxious, irritant, and inflammatory stimuli. Activation of these nerves triggers protective mechanisms that lead to withdrawal from danger (pain), removal of irritants (itch, cough), and resolution of infection (neurogenic inflammation). The GPCR-TRP axis is central to these mechanisms. Signals that emanate from the GPCR superfamily converge on the small TRP family, leading to channel sensitization and activation, which amplify pain, itch, cough, and neurogenic inflammation. Herein we discuss how GPCRs and TRP channels function independently and synergistically to excite sensory nerves that mediate noxious and irritant responses and inflammation in the skin and the gastrointestinal and respiratory systems. We discuss the signaling mechanisms that underlie the GPCR-TRP axis and evaluate how new information about the structure of GPCRs and TRP channels provides insights into their functional interactions. We propose that a deeper understanding of the GPCR-TRP axis may facilitate the development of more selective and effective therapies to treat dysregulated processes that underlie chronic pain, itch, cough, and inflammation.
authors.affiliation: Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia (N.A.V., D.P.P., N.W.B); Departments of Genetics (N.A.V.), Anatomy and Neuroscience (D.P.P.), and Pharmacology (N.W.B.), The University of Melbourne, Melbourne, Victoria, Australia; School of Medical Sciences and Health Innovations Research Institute, RMIT University, Bundoora, Victoria, Australia (M.G., P.M.); and ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash University, Parkville, Victoria, Australia (N.W.B.).
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Veldhuis
authors.affiliation: Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia (N.A.V., D.P.P., N.W.B); Departments of Genetics (N.A.V.), Anatomy and Neuroscience (D.P.P.), and Pharmacology (N.W.B.), The University of Melbourne, Melbourne, Victoria, Australia; School of Medical Sciences and Health Innovations Research Institute, RMIT University, Bundoora, Victoria, Australia (M.G., P.M.); and ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash University, Parkville, Victoria, Australia (N.W.B.).
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Poole
authors.affiliation: Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia (N.A.V., D.P.P., N.W.B); Departments of Genetics (N.A.V.), Anatomy and Neuroscience (D.P.P.), and Pharmacology (N.W.B.), The University of Melbourne, Melbourne, Victoria, Australia; School of Medical Sciences and Health Innovations Research Institute, RMIT University, Bundoora, Victoria, Australia (M.G., P.M.); and ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash University, Parkville, Victoria, Australia (N.W.B.).
authors.forename: Megan
authors.initials: M
authors.lastname: Grace
authors.affiliation: Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia (N.A.V., D.P.P., N.W.B); Departments of Genetics (N.A.V.), Anatomy and Neuroscience (D.P.P.), and Pharmacology (N.W.B.), The University of Melbourne, Melbourne, Victoria, Australia; School of Medical Sciences and Health Innovations Research Institute, RMIT University, Bundoora, Victoria, Australia (M.G., P.M.); and ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash University, Parkville, Victoria, Australia (N.W.B.).
authors.forename: Peter
authors.initials: P
authors.lastname: McIntyre
authors.affiliation: Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia (N.A.V., D.P.P., N.W.B); Departments of Genetics (N.A.V.), Anatomy and Neuroscience (D.P.P.), and Pharmacology (N.W.B.), The University of Melbourne, Melbourne, Victoria, Australia; School of Medical Sciences and Health Innovations Research Institute, RMIT University, Bundoora, Victoria, Australia (M.G., P.M.); and ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash University, Parkville, Victoria, Australia (N.W.B.) Nigel.Bunnett@Monash.edu.
authors.forename: Nigel W
authors.initials: NW
authors.lastname: Bunnett
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D015195:Drug Design; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D008024:Ligands; D058990:Molecular Targeted Therapy; D017288:Pain Threshold; D020239:Receptor Cross-Talk / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D012678:Sensation Disorders / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism*; D018689:Sensory System Agents / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D050051:Transient Receptor Potential Channels / Q000187:drug effects / Q000378:metabolism*; D014781:Viscera / Q000294:innervation
chemical_list: D000893:Anti-Inflammatory Agents; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D018689:Sensory System Agents; D050051:Transient Receptor Potential Channels