N-Palmitoyl glycine activates transient receptor potential channel 5 and increases the risk of Brugada syndrome

Background Brugada syndrome (BrS) is an arrhythmic disorder associated with an increased risk of sudden cardiac death; however, current treatment options are limited due to their side effects and variable efficacy. Methods In this study, we first employed Mendelian randomization analysis utilizing proteomic, transcriptomic, and metabolomic data to identify potential therapeutic targets for BrS. Ex vivo perfused heart models were used to assess the effects of the potential targets on action potentials and QT intervals. Calcium indicators were employed to evaluate calcium homeostasis in primary cardiomyocytes, and patch-clamp techniques were used to investigate the impact on Nav1.5 and TRPC5 channels. Results Our findings indicate that N-palmitoyl glycine (PalGly) is linked to an increased risk of BrS and interacts with BrS-associated proteins, demonstrating moderate binding affinities for DCC, CR1, CTSB, NAAA, DEFB1, EPHA1, IGF1/IGFBP3/ALS, and LTA. Electrophysiological experiments showed that although PalGly does not interact with Nav1.5, it enhances calcium sparks in ventricular cardiomyocytes. We determined that the calcium-modulating effect of PalGly is mediated by its binding to and activation of the transient receptor potential channel 5 (TRPC5) channel. Furthermore, PalGly was found to shorten the QT interval and action potential duration in Langendorff-perfused rabbit hearts and isolated rabbit cardiomyocytes. Transcriptomic and lipidomic analyses of PalGly-treated neonatal rat cardiomyocytes revealed significant negative modulation of immune pathways, akin to the effects observed with agonizing TRPC5. Conclusion Our study underscores the involvement of PalGly, TRPC5, and inflammation-related proteins in the pathophysiology of BrS.