Ca2+ Influx through TRPC Channels Is Regulated by Homocysteine–Copper Complexes

Chen, Gui-Lan; Zeng, Bo; Jiang, Hongni; Daskoulidou, Nikoleta; Saurabh, Rahul; Chitando, Rumbidzai J; Xu, Shang-Zhong

Abstract

An elevated level of circulating homocysteine (Hcy) has been regarded as an independent risk factor for cardiovascular disease; however, the clinical benefit of Hcy lowering-therapy is not satisfying. To explore potential unrevealed mechanisms, we investigated the roles of Ca2+ influx through TRPC channels and regulation by Hcy–copper complexes. Using primary cultured human aortic endothelial cells and HEK-293 T-REx cells with inducible TRPC gene expression, we found that Hcy increased the Ca2+ influx in vascular endothelial cells through the activation of TRPC4 and TRPC5. The activity of TRPC4 and TRPC5 was regulated by extracellular divalent copper (Cu2+) and Hcy. Hcy prevented channel activation by divalent copper, but monovalent copper (Cu+) had no effect on the TRPC channels. The glutamic acids (E542/E543) and the cysteine residue (C554) in the extracellular pore region of the TRPC4 channel mediated the effect of Hcy–copper complexes. The interaction of Hcy–copper significantly regulated endothelial proliferation, migration, and angiogenesis. Our results suggest that Hcy–copper complexes function as a new pair of endogenous regulators for TRPC channel activity. This finding gives a new understanding of the pathogenesis of hyperhomocysteinemia and may explain the unsatisfying clinical outcome of Hcy-lowering therapy and the potential benefit of copper-chelating therapy.

Citation

Chen, G., Zeng, B., Jiang, H., Daskoulidou, N., Saurabh, R., Chitando, R. J., & Xu, S. (2023). Ca2+ Influx through TRPC Channels Is Regulated by Homocysteine–Copper Complexes. Biomolecules, 13(6), Article 952. https://doi.org/10.3390/biom13060952

• Journal Article Type: Article
• Acceptance Date: May 17, 2023
• Online Publication Date: Jun 6, 2023
• Publication Date: Jun 1, 2023
• Deposit Date: Jan 24, 2024
• Publicly Available Date: Jan 25, 2024
• Journal: Biomolecules
• Electronic ISSN: 2218-273X
• Publisher: MDPI
• Peer Reviewed: Peer Reviewed
• Volume: 13
• Issue: 6
• Article Number: 952
• DOI: https://doi.org/10.3390/biom13060952
• Keywords: Homocysteine; Calcium channel; TRPC; TRPM2; Copper; Endothelial cells; Angiogenesis; 2-aminoethoxydiphenyl borate
• Public URL: https://hull-repository.worktribe.com/output/4525288