2026-04-27T14:40:07Zhttps://uvadoc.uva.es/oai/request

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

00925njm 22002777a 4500 dc Casas Requena, Javier author Meana González, Clara author López López, José Ramón author Balsinde Rodríguez, Jesús author Balboa García, María Ángeles author 2021 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. Cellular and Molecular Life Science, 2021, vol. 78, p. 8243-8260. 1420-682X https://uvadoc.uva.es/handle/10324/65532 10.1007/s00018-021-03999-0 8243 24 8260 Cellular and Molecular Life Sciences 78 1420-9071 Lipin-1-derived diacylglycerol activates intracellular TRPC3 which is critical for inflammatory signaling