P2ry14, a rhodopsin-like G-protein-coupled receptor, is the UDP-glucose-specific G(i) protein-coupled P2Y receptor. It signals via Gi to increase intracellular cAMP. P2ry14 is involved in multiple biological processes and is expressed in various cell types such as Schwann cell precursors, renal collecting duct principal cells, and hepatic stellate cells [1,2,4].

In a mouse model of neurofibromatosis type 1 (NF1), genetic deletion of P2ry14 rescued low cAMP signaling, increased mouse survival, delayed neurofibroma initiation, and improved SC Remak bundles. Also, when SC lacked Nf1, genetic loss or pharmacological inhibition of P2ry14 rescued Cav1 expression and blood-nerve-barrier function [1,3]. In P2ry14-deficient mice, there was a reduced urine volume and changed renal sphingolipid metabolism, suggesting its functional importance in renal collecting duct principal cells [2]. In the liver, global and HSC-selective P2Y14 deficiency attenuated liver fibrosis in multiple mouse models of liver injury, as P2Y14 ligands and their receptor link hepatocyte death to hepatic stellate cell activation and fibrogenesis [4].

In conclusion, P2ry14 is crucial in regulating cAMP signaling, cell self-renewal, proliferation, and tissue-specific functions. Gene-knockout mouse models have revealed its significant roles in diseases like neurofibromatosis, kidney function-related conditions, and liver fibrosis, providing potential therapeutic targets for these diseases.

References:

1. Patritti Cram, Jennifer, Wu, Jianqiang, Coover, Robert A, Spinner, Robert J, Ratner, Nancy. 2022. P2RY14 cAMP signaling regulates Schwann cell precursor self-renewal, proliferation, and nerve tumor initiation in a mouse model of neurofibromatosis. In eLife, 11, . doi:10.7554/eLife.73511. https://pubmed.ncbi.nlm.nih.gov/35311647/

2. Baalmann, Fabian, Brendler, Jana, Butthof, Anne, Schöneberg, Torsten, Schulz, Angela. 2023. Reduced urine volume and changed renal sphingolipid metabolism in P2ry14-deficient mice. In Frontiers in cell and developmental biology, 11, 1128456. doi:10.3389/fcell.2023.1128456. https://pubmed.ncbi.nlm.nih.gov/37250906/

3. Patritti-Cram, Jennifer, Rahrmann, Eric P, Rizvi, Tilat A, Largaespada, David A, Ratner, Nancy. 2024. NF1-dependent disruption of the blood-nerve-barrier is improved by blockade of P2RY14. In iScience, 27, 110294. doi:10.1016/j.isci.2024.110294. https://pubmed.ncbi.nlm.nih.gov/39100928/

4. Mederacke, Ingmar, Filliol, Aveline, Affo, Silvia, Sancho-Bru, Pau, Schwabe, Robert F. 2022. The purinergic P2Y14 receptor links hepatocyte death to hepatic stellate cell activation and fibrogenesis in the liver. In Science translational medicine, 14, eabe5795. doi:10.1126/scitranslmed.abe5795. https://pubmed.ncbi.nlm.nih.gov/35385339/