2026-05-14T13:06:33Zhttps://uvadoc.uva.es/oai/request

oai:uvadoc.uva.es:10324/655322025-03-07T08:45:49Zcom_10324_1134com_10324_931com_10324_894col_10324_1213

Lipin-1-derived diacylglycerol activates intracellular TRPC3 which is critical for inflammatory signaling Casas Requena, Javier Meana González, Clara López López, José Ramón Balsinde Rodríguez, Jesús Balboa García, María Ángeles TRPC3 Lipin-1 Macrophages Inflammation DAG Ca2+ release Producción Científica Exposure to Gram-negative bacterial LPS exacerbates host immune responses and may lead to sepsis, a life-threatening condition. Despite its high mortality and morbidity, no drugs specifically directed to treating sepsis are currently available. Using human cell genetic depletion, pharmacological inhibition, live-cell microscopy and organelle-targeted molecular sensors we present evidence that the channel TRPC3 is activated intracellularly during macrophage exposure to LPS and is essential for Ca2+ release from internal stores. In this manner, TRPC3 participates in cytosolic Ca2+ elevations, activation of the transcription factor NF-κB and cytokine upregulation. We also report that TRPC3 is activated by diacylglycerol generated by the phosphatidic acid phosphatase lipin-1. In accord with this, lipin-1-deficient cells exhibit reduced Ca2+ responses to LPS challenge. Finally, pharmacological inhibition of TRPC3 reduces systemic inflammation induced by LPS in mice. Collectively, our study unveils a central component of LPS-triggered Ca2+ signaling that involves intracellular sensing of lipin-1-derived DAG by TRPC3, and opens new opportunities for the development of strategies to treat LPS-driven inflammation. 2024-02-01T15:02:57Z 2024-02-01T15:02:57Z 2021 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion https://doi.org/10.1007/s00018-021-03999-0 Cellular and Molecular Life Science, 2021, vol. 78, p. 8243-8260. 1420-682X https://uvadoc.uva.es/handle/10324/65532 8243 24 8260 Cellular and Molecular Life Sciences 78 1420-9071 eng https://link.springer.com/article/10.1007/s00018-021-03999-0 Atribución 4.0 Internacional info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by/4.0/ application/pdf