Xinzhong Dong, PhD
Professor, Department of Neuroscience,
Johns Hopkins University
Host: Jun Ding
Despite of the clinical importance, cell surface receptors mediating non-histaminergic itch are largely unknown. We identified a large family of G protein-coupled receptors in mice called Mrgprs. Several of these receptors are specifically expressed in distinct subsets of small-diameter dorsal root ganglion (DRG) neurons and function as novel itch receptors mediating histamine-independent itch. For example, we recently identified that MrgprA1 is a receptor for bilirubin and plays an important role in jaundice (a yellowing of the skin due to a buildup of bilirubin)-associated itch. Patients with jaundice commonly suffer from an intense non-histaminergic itch. We demonstrated for the first time the existence of bilirubin receptors (MrgprA1 in mice and MrgprX4 in humans) and that pathophysiologic levels of bilirubin elicit itch through MrgprA1 in primary sensory neurons in the DRG. In mouse models of pathologic hyperbilirubinemias, we showed that genetic deletion of either Mrgpra1 or BVR, the bilirubin-producing enzyme, attenuates itch. Plasma isolated from hyperbilirubinemic patients evoked itch in wild-type animals but not Mrgpra1-/- animals. Besides the sensory neuron specific Mrgprs, we and others discovered another member of the gene family, MrgprB2 in mice and its human homologue MrgprX2, are exclusively expressed in mast cells, a type of innate immune cells, which secret many pro-inflammatory mediators upon activation. We demonstrated that MrgprB2/MrgprX2 are receptors for various basic secretogagues and mediate IgE-independent mast cell degranulation. Recently we found that MrgprB2 plays an important role in neurogenic inflammation and pain by acting as a receptor for the pro-inflammatory peptide substance P released from sensory nerves. Therefore, we believe that targeting Mrgprs may lead to novel treatment of chronic itch and pain in the future.
 J Meixiong, C Vasavda, D Green, Q Zheng, L Qi, SG Kwatra, JP Hamilton, SH Snyder, X Dong. Identification of a bilirubin receptor that may mediate a component of cholestatic itch. 2019 eLife 8: e44116. doi: 10.7554/eLife.44116