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

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. In this study, we employed Mendelian randomization analysis utilizing proteomic, transcriptomic, and metabolomic data to identify potential therapeutic targets for BrS. Our findings indicate that N-palmitoylglycine (PalGly) is linked to an increased risk of BrS and interacts with BrS-associated proteins, demonstrating moderate binding affinities for proteins such as DCC, CR1, CTSB, NAAA, DEFB1, EPHA1, IGF1/IGFBP3/ALS, and LTA. 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 ventricular cardiomyocytes. Transcriptomic and lipidomic analyses of PalGly-treated neonatal rat cardiomyocytes revealed significant modulation of immune pathways, akin to the effects observed with TRPC5 agonists. Collectively, our study underscores the involvement of PalGly and TRPC5 in the pathophysiology of BrS. Overall design: To investigate the cardiac effect of N-palmitoylglycine, we extracted neonatal rat cardiomyocytes and stimulated these cells with 1 µM N-palmitoylglycine 24h hours.