2. Academic Validation
  3. N-palmitoyl glycine differentially modulates TRPM4 and TRPC5 and is causally linked to Brugada syndrome

N-palmitoyl glycine differentially modulates TRPM4 and TRPC5 and is causally linked to Brugada syndrome

  • Commun Biol. 2025 Nov 28. doi: 10.1038/s42003-025-09296-x.
Hongxuan Xu # 1 2,  Bingxun Li # 1 2 3,  Ying Chen 1 2,  Yanyun Lin 1 2,  An Zhang 1 2,  Lin Wu 4 5 6
Affiliations

Affiliations

  • 1 Department of Cardiology, Peking University First Hospital, Beijing, China.
  • 2 State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China.
  • 3 Department of Cardiology, The First College of Clinical Medical Science, China Three Gorges University & Yichang Central People's Hospital, Yichang, China.
  • 4 Department of Cardiology, Peking University First Hospital, Beijing, China. [email protected].
  • 5 State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China. [email protected].
  • 6 Key Laboratory of Medical Electrophysiology of the Ministry of Education, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China. [email protected].
  • # Contributed equally.
PMID: 41315851 DOI: 10.1038/s42003-025-09296-x
Abstract

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 Nav1.5 or Kv4.3/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.

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