Scientists found that a molecule called N‑palmitoyl glycine can affect heart cells by turning on a channel called TRPC5 and blocking another called TRPM4, which together can shorten the heart's electrical signals and may be linked to a dangerous heart rhythm problem called Brugada syndrome.

Brugada syndrome (BrS) is an inherited cardiac arrhythmic disorder associated with an increased risk of malignant ventricular arrhythmia and sudden death. Mendelian randomisation implicated N-palmitoyl glycine (PalGly) in BrS risk and identified BrS-associated proteins (DCC, CR1, CTSB, NAAA, DEFB1, EPHA1, IGF1/IGFBP3/ALS, and LTA), for which molecular docking further predicted moderate binding affinities with PalGly. PalGly enhanced calcium sparks in ventricular cardiomyocytes without affecting Na_v1.5 or K_v4.3/KChiP2 but activated TRPC5 (EC₅₀ 104 nM), as confirmed by patch-clamp. TRPM4, a channel mediating sodium influx at negative potentials and reported to link to BrS when mutated, was directly inhibited by PalGly (IC₅₀ = 7 nM). Functionally, PalGly shortened APD in cardiomyocytes and QT in male rabbit hearts, whereas ML204 (TRPC5 inhibitor) further shortened APD in isolated cardiomyocytes. Transcriptomic and lipidomic analyses further indicated immune pathway suppression. Our study underscores the involvement of PalGly, TRPC5, and inflammation-related proteins in the pathophysiology of BrS.