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How the spinal cord transmits heat signals from the periphery to the brain remains unclear. In this issue of Neuron , Wang et al. (2022) identify a population of spinal cord neurons functioning in this pathway. [ABSTRACT FROM AUTHOR]

Chronic itch is a debilitating symptom profoundly impacting the quality of life in patients with liver diseases like cholestasis. Activation of the human G-protein coupled receptor, MRGPRX4 (hX4), by bile acids (BAs) is implicated in promoting cholestasis itch. However, the detailed underlying mechanisms remain elusive. Here, we identified 3-sulfated BAs that are elevated in cholestatic patients with itch symptoms. We solved the cryo-EM structure of hX4-Gq in a complex with 3-phosphated deoxycholic acid (DCA-3P), a mimic of the endogenous 3-sulfated deoxycholic acid (DCA-3S). This structure revealed an unprecedented ligand-binding pocket in MRGPR family proteins, highlighting the crucial role of the 3-hydroxyl (3-OH) group on BAs in activating hX4. Guided by this structural information, we designed and developed compound 7 (C7), a BA derivative lacking the 3-OH. Notably, C7 effectively alleviates hepatic injury and fibrosis in liver disease models while significantly mitigating the itch side effects. [Display omitted] • 3-sulfated bile acids accumulate in cholestatic patients, causing itch symptoms • The cryo-EM structure of MRGPRX4 (hX4) with DCA-3P unveils how bile acids activate hX4 • Obeticholic acid (OCA) induces an itch side effect by activating hX4 • An OCA derivative, C7, was developed to treat liver diseases without causing itch Bile acids (BAs) are 3-sulfonated to improve their potency to activate MRGPRX4 (hX4), the G-protein-coupled receptor for cholestatic itch. The cryo-EM structure of hX4 binding with a bile acid-derived agonist highlights the importance of the 3-hydroxyl group in BAs to activate hX4 and helps develop the lead compound, C7, as a promising candidate for treating liver diseases without the unwanted side effect of itch. [ABSTRACT FROM AUTHOR]