Researchers in the department of Pharmacology link orphan receptor MRGRPX2 to opioid-induced itching and create a tool to study the receptor more precisely.
New findings published in the journal by 黑料网 scientists in the department of pharmacology show that MRGRPX2, a receptor protein on the surface of mast cells, can trigger the immune system response that leads to itching associated with some opioids.
Kate Lansu, the paper鈥檚 first co-author and a graduate student in the lab of Bryan Roth, MD, PhD, explains how this process works.
鈥淩eceptors in mast cells 鈥� part of the immune system 鈥� respond to an activation signal and release inflammatory factors like histamine, in a process called degranulation,鈥� she said. 鈥淲hen that happens, other cells are recruited to the site of inflammation to clear the infection. This response is also important for things like allergies. And this is what presents itself as itching.鈥�
鈥淥pioid drugs have been link to degranulation also, but it was through an unknown mechanism. We think that our data could potentially explain why degranulation occurs as a side effect of opioid ligands (morphine and other drugs), something that is well-known but not well-understood.鈥�
鈥淲e start with the physical screening data to give us a sense of what types of molecules interact with the receptor,鈥� Lansu said. 鈥淲orking on MRGRPX2, I screened around 7,000 molecules, and that data gave us a sense of what the binding site might look like. Once that tentative picture was in place, we were able to use computational tools to create a more precise model of the site.鈥�
Understanding what triggers the itching response could help pharmacologists develop an antagonist for this receptor to reduce the itching side effect. In other cases, clinicians may want to induce histamine release, thereby boosting the immune response, as in the case of vaccine adjuvants, where an increased immune response may improve immunity.
Abstract
The primate-exclusive MRGPRX2 G protein-coupled receptor (GPCR) has been suggested to modulate pain and itch. Despite putative peptide and small-molecule MRGPRX2 agonists, selective nanomolar-potency probes have not yet been reported. To identify a MRGPRX2 probe, we first screened 5,695 small molecules and found that many opioid compounds activated MRGPRX2, including (-)- and (+)-morphine, hydrocodone, sinomenine, dextromethorphan, and the prodynorphin-derived peptides dynorphin A, dynorphin B, and 伪- and 尾-neoendorphin. We used these to select for mutagenesis-validated homology models and docked almost 4 million small molecules. From this docking, we predicted ZINC-3573-a potent MRGPRX2-selective agonist, showing little activity against 315 other GPCRs and 97 representative kinases-along with an essentially inactive enantiomer. ZINC-3573 activates endogenous MRGPRX2 in a human mast cell line, inducing degranulation and calcium release. MRGPRX2 is a unique atypical opioid-like receptor important for modulating mast cell degranulation, which can now be specifically modulated with ZINC-3573.
Citation
Lansu K, Karpiak J, Liu J, Huang XP, McCorvy JD, Kroeze WK, Che T, Nagase H, Carroll FI, Jin J, Shoichet BK, Roth BL. Nat Chem Biol. 2017 Mar 13. doi:
10.1038/nchembio.2334. [Epub ahead of print] PubMed PMID: 28288109.
Other 黑料网 authors on the paper are: Xi-Ping Huang, PhD, and Wesley K. Kroze, PhD, research assistant professors in the 黑料网 department of Pharmacology; 黑料网 research associates John D. McCorvy, PhD, and Tao Che, PhD, also in the 黑料网 department of Pharmacology; and senior author, Bryan Roth, MD, PhD, Michael Hooker Distinguished Professor of Protein Therapeutics and Translational Proteomics in the department of Pharmacology, who has a joint appointment at the 黑料网 Eshelman School of Pharmacy.