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MRGPRX4 Is a G Protein-Coupled Receptor Activated by Bile Acids That May Contribute to Cholestatic Pruritus

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MRGPRX4 Is a G Protein-Coupled Receptor Activated by Bile Acids That May Contribute to Cholestatic Pruritus MRGPRX4 is a G protein-coupled receptor activated by bile acids that may contribute to cholestatic pruritus James Meixionga, Chirag Vasavdaa, Solomon H. Snydera,b,c,1, and Xinzhong Donga,d,e,f,1 aSolomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; bDepartment of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; cDepartment of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; dDepartment of Dermatology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; eDepartment of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; and fHoward Hughes Medical Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21205 Contributed by Solomon H. Snyder, April 5, 2019 (sent for review February 26, 2019; reviewed by Hongzhen Hu and Gil Yosipovitch) Patients suffering from cholestasis, the slowing or stoppage of bile BA-induced itch is likely not TGR5 dependent in humans, a flow, commonly report experiencing an intense, chronic itch. scenario different from mice. Numerous pruritogens are up-regulated in cholestatic patient sera, Cholestatic pruritus is classified as nonhistaminergic itch. including bile acids (BAs). Acute injection of BAs results in itch in Cholestatic patients do not exhibit classic signs of histamine re- both mice and humans, and BA-modulating therapy is effective in lease, such as erythema or swelling (3). Moreover, antihistamines controlling patient itch. Here, we present evidence that human are ineffective in treating cholestatic pruritus, with only a few sensory neuron-expressed Mas-related G protein-coupled receptor patients reporting clinical improvement in their symptoms (3, X4 (MRGPRX4), an orphan member of the Mrgpr family of GPCRs, 2+ 19). The Mas-related family of G protein-coupled receptors is a BA receptor. Using Ca imaging, we determined that pathophy- (MRGPRs) are GPCRs that mediate nonhistaminergic itch. In siologically relevant levels of numerous BAs activated MRGPRX4. No mice, MRGPRs are expressed in small-diameter sensory neurons mouse Mrgpr orthologs were activated by BAs. To assess the in vivo that code exclusively for itch and not pain (20). Over the years, relevance of BA activation of MRGPRX4, we generated a humanized increasingly more members of the MRGPR family have been mouse with targeted expression of MRGPRX4 in itch-encoding sen- + identified as receptors for known pruritogens (21). sory neurons. BAs activated MRGPRX4 sensory neurons at higher In mice, there are 27 expressed Mrgprs, only a few of which NEUROSCIENCE levels compared with WT neurons. Compared with control animals, + have known ligands (22). In humans, there are eight expressed MRGPRX4 mice scratched more upon acute injection of BAs and in a – – model of cholestatic itch. Overall, these data suggest that targeting Mrgprs (MRGPRX1 X4 and -D G). MRGPRX1 and MRGPRD MRGPRX4 is a promising strategy for alleviating cholestatic itch. have been implicated in nonhistaminergic itch as receptors for pruritic compounds. MRGPRX1, -X3, -X4, -D, and -E are cholestasis | itch | pruritus | MRGPRX4 | bile acids expressed in human dorsal root ganglia (DRG) and trigeminal ganglia (TG), while MRGPRX2 has been detected in human – n the United States, hundreds of thousands of patients report mast cells (23 26). Recently, we have identified murine receptor Iexperiencing a severe, generalized pruritus (itch) due to cho- Mrgpra1 and human receptor MRGPRX4 as receptors for bili- lestasis, or the slowing or stoppage of bile flow. Cholestatic itch is rubin that may mediate a component of cholestatic itch (27). often nonresponsive to standard pharmacological treatments (1– 3) and instead requires physically removing the causative ob- Significance struction (such as gallstones), draining the bile, or transplanting the liver to alleviate itch (1, 4, 5). Because these procedures are Cholestatic itch is a debilitating symptom that affects hundreds often curative, the responsible pruritogens are hypothesized to of thousands of patients every year, drastically decreasing originate from the liver and bile. Numerous candidate pruri- patient quality of life. Additional therapeutic targets are togens are present in bile and up-regulated in cholestatic pa- needed, as current therapies are ineffective for many patients. tients, including opioids, lysophosphatidic acid, bilirubin, and In recent years, the Mas-related G protein-coupled receptor bile acids (BAs). Therapies targeting these mechanisms, such as (MRGPR) family of receptors has been linked to itch. Here, we opioid antagonists, rifampicin, and BA-binding resins like cho- determine that MRGPRX4 is specifically activated by numerous lestyramine, are frontline therapy for cholestatic itch (6–9). bile acids (BAs) up-regulated in cholestatic patient sera. To test the relevance of these findings in vivo, we generated human- BAs are amphipathic cholesterol derivatives synthesized in + ized mice expressing MRGPRX4 in sensory neurons. MRGPRX4 liver. BAs have previously defined roles as detergents, hormones, humanized mice display higher levels of itch in response to and antiinflammatory agents (10–13). Primary BA synthesis aids injection of BAs and in a mouse model of cholestasis, indicating in biliary secretion of phospholipids, drugs, and toxins. In liver, that MRGPRX4 could play a role in cholestatic itch. BAs are conjugated with taurine or glycine for biliary secretion. Secreted BAs can be reabsorbed in the ileum and retrogradely Author contributions: J.M. designed research; J.M. and C.V. performed research; J.M. and transported to liver where they inhibit synthesis in an inhibitory C.V. analyzed data; J.M., C.V., S.H.S., and X.D. wrote the paper; and S.H.S. and X.D. feedback loop. In cholestatic patients, BAs accumulate in both supervised the research. serum and tissue because bile flow is abrogated. Reviewers: H.H., Washington University School of Medicine in St. Louis; and G.Y., Univer- BAs are pruritic as injecting BAs in humans evokes itch (14, sity of Miami Miller School of Medicine. 15). In mice, TGR5, a G protein-coupled receptor (GPCR) with Conflict of interest statement: J.M. is a consultant for Escient Pharmaceuticals, a company focused on developing small molecule inhibitors for MRGPRs. X.D. is a co-founder of micromolar affinity toward BAs (16, 17), is expressed in itch Escient Pharmaceuticals. −/− sensory neurons (10). TGR5 mice scratched less in response Published under the PNAS license. to injection of multiple activating BAs, indicating that the re- 1To whom correspondence may be addressed. Email: [email protected] or xdong2@jhmi. ceptor mediates a component of acute BA-associated itch (10). edu. However, recent clinical trials have found that TGR5-specific This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. agonists do not elicit pruritus, suggesting that activating TGR5 1073/pnas.1903316116/-/DCSupplemental. alone is not sufficient to evoke itch in humans (18). Accordingly, Published online May 8, 2019. www.pnas.org/cgi/doi/10.1073/pnas.1903316116 PNAS | May 21, 2019 | vol. 116 | no. 21 | 10525–10530 Downloaded by guest on October 1, 2021 + Another published MRGPRX4 agonist, nateglinide, is a clini- MRGPRX4-induced Ca2 signal was dependent on intracellular + cally approved type 2 diabetes drug that causes itch as a prom- Ca2 stores. Previous studies have identified MRGPRX4 as be- inent side effect (28, 29), further implicating MRGPRX4 as an ing Gαq linked (27, 29). In line with this, DCA-associated 2+ itch receptor. In this study, we screened major bile constituents Ca flux appears to be similarly Gαq linked, since both the against a panel of both mouse and human MRGPRs. From this Gαq inhibitor, YM254890, and the PLC inhibitor, U73122, + screen, we determined that numerous BAs specifically activated inhibited Ca2 signal (Fig. 1 G and H). MRGPRX4. Of all mouse and human receptors tested, BAs only Of the BAs tested, DCA and ursodeoxycholic acid (UDCA) activated MRGPRX4. Using newly generated humanized mice displayed the highest potency in terms of MRGPRX4-associated + in which we express MRGPRX4 selectively in itch-sensing neu- Ca2 signal (Fig. 1C and SI Appendix, Fig. S1F). Both DCA and rons, we demonstrated that MRGPRX4 contributed to the BA- UDCA had EC50sof∼5 μM, similar to their activity toward induced component of cholestatic itch. previously published receptors like TGR5 (17). Unlike TGR5, however, MRGPRX4 exhibited a larger range of potency for Results various BAs. For example, cholic acid (CA) displayed much In liver hepatocytes, cholesterol is metabolized via cytochrome lower potency against MRGPRX4 (EC50 ∼430 μM), well outside P450 (CYP) to primary BAs (Fig. 1A). Primary BAs are sub- physiologic range. In contrast, the EC50 of CA toward TGR5 is sequently metabolized to other BAs, after which they are con- ∼10 μM (17). jugated to either glycine or taurine for more efficient biliary Primary bile acids can be conjugated to either glycine or taurine secretion. In the intestine, bacteria metabolize BAs to form to form water-soluble bile salts. We tested three tauro-conjugated secondary BAs, which can return to the bloodstream and liver bile acids, tauro-DCA (TDCA), tauro-CDCA (TCDCA), and through enterohepatic circulation (Fig. 1A). We recently iden- tauro-cholic acid (TCA) against MRGPRX4. All conjugated bile tified
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