TRPA1 is required for histamine-independent, Mas-related G protein-coupled receptor-mediated itch

• Published in: Nature neuroscience Vol. 14; no. 5; pp. 595 - 602
• Main Authors: Bautista, Diana M, Wilson, Sarah R, Gerhold, Kristin A, Bifolck-Fisher, Amber, Liu, Qin, Patel, Kush N, Dong, Xinzhong
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-05-2011; Nature Publishing Group
• Subjects: 631/378/2586; 631/378/2620/410; 631/80/86; 692/1807/1812; Analysis of Variance; Animal Genetics and Genomics; Animals; Animals, Newborn; Antirheumatic Agents; Behavioral Sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Calcium - metabolism; Capsaicin - pharmacology; Cells, Cultured; Cellular signal transduction; Chloroquine; Disease Models, Animal; Drug Interactions; Enzyme Inhibitors - pharmacology; G proteins; Ganglia, Spinal - cytology; Gene Expression Regulation - drug effects; Genetic aspects; Histamine; Histamine - adverse effects; Membrane Potentials - drug effects; Mice; Mice, Knockout; Mustard Plant; Nervous system; Nervous system diseases; Neurobiology; Neuroblastoma - pathology; Neurons; Neurosciences; Patch-Clamp Techniques; Peptides - pharmacology; Physiological aspects; Plant Oils - pharmacology; Pruritus; Pruritus - chemically induced; Pruritus - drug therapy; Pruritus - metabolism; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Risk factors; Sensory Receptor Cells - drug effects; Sensory Receptor Cells - metabolism; Signal Transduction - physiology; Time Factors; Transfection - methods; Transient Receptor Potential Channels - deficiency; Transient Receptor Potential Channels - metabolism; TRPA1 Cation Channel; United States; United States > US; California
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/nn.2789

Previous work has shown that two members of the Mas-related GPCR family, MrgprA3 and MrgprC11, mediate histamine-independent itch signaling. Here, Wilson
et al
. demonstrate that TRPA1 is a downstream target of both of these receptors in sensory neurons and is required for Mrgpr-evoked itch.
Itch, the unpleasant sensation that evokes a desire to scratch, accompanies numerous skin and nervous system disorders. In many cases, pathological itch is insensitive to antihistamine treatment. Recent studies have identified members of the Mas-related G protein–coupled receptor (Mrgpr) family that are activated by mast cell mediators and promote histamine-independent itch. MrgprA3 and MrgprC11 act as receptors for the pruritogens chloroquine and BAM8–22, respectively. However, the signaling pathways and transduction channels activated downstream of these pruritogens are largely unknown. We found that TRPA1 is the downstream target of both MrgprA3 and MrgprC11 in cultured sensory neurons and heterologous cells. TRPA1 is required for Mrgpr-mediated signaling, as sensory neurons from TRPA1-deficient mice exhibited markedly diminished responses to chloroquine and BAM8–22. Similarly, TRPA1-deficient mice displayed little to no scratching in response to these pruritogens. Our findings indicate that TRPA1 is an essential component of the signaling pathways that promote histamine-independent itch.