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.布鲁加达综合征（Brugada syndrome, BrS）是一类与心源性猝死风险升高相关的心律失常性疾病，但当前治疗方案因副作用显著、疗效参差不齐而选择有限。本研究利用蛋白质组学、转录组学及代谢组学数据开展孟德尔随机化分析，旨在挖掘布鲁加达综合征的潜在治疗靶点。研究结果显示，N-棕榈酰甘氨酸（N-palmitoylglycine, PalGly）与布鲁加达综合征风险升高存在关联，且可与布鲁加达综合征相关蛋白相互作用，对DCC、CR1、CTSB、NAAA、DEFB1、EPHA1、IGF1/IGFBP3/ALS及LTA等蛋白展现出中等结合亲和力。尽管PalGly无法与Nav1.5结合，但它可增强心室肌细胞的钙火花信号。进一步研究证实，PalGly的钙调节效应是通过结合并激活瞬时受体电位通道5（transient receptor potential channel 5, TRPC5）实现的。此外，PalGly可缩短朗德多克灌流兔心脏及心室肌细胞的QT间期与动作电位时程。对经PalGly处理的新生大鼠心肌细胞进行转录组学与脂质组学分析后发现，其可显著调控免疫通路，这一效应与TRPC5激动剂的作用相似。综上，本研究明确了PalGly与TRPC5在布鲁加达综合征病理生理过程中的参与作用。