Transient Ca2+ entry by plasmalogen-mediated activation of receptor potential cation channel promotes AMPK activity

Abstract

Ethanolamine-containing alkenyl ether glycerophospholipids, plasmalogens, are major cell membrane components of mammalian cells that activate membrane protein receptors such as ion transporters and G-protein coupled receptors. However, the mechanism by which plasmalogens modulate receptor function is unknown. Here, we found that exogenously added plasmalogens activate transient receptor potential cation channel subfamily C member 4 (TRPC4) to increase Ca2+ influx, followed by calcium/calmodulin-dependent protein kinase 2-mediated phosphorylation of AMP-activated protein kinase (AMPK). Upon topical application of plasmalogens to the skin of mice, AMPK activation was observed in TRPC4-expressing hair bulbs and hair follicles. Here, TRPC4 was co-localized with the leucine-rich repeat containing G protein-coupled receptor 5, a marker of hair-follicle stem cells, leading to hair growth. Collectively, this study indicates that plasmalogens could function as gate openers for TRPC4, followed by activating AMPK, which likely accelerates hair growth in mice.

High coverage of targeted lipidomics revealed lipid changes in the follicular fluid of patients with insulin-resistant polycystic ovary syndrome and a positive correlation between plasmalogens and oocyte quality

“…Eicosapentaenoic acid-enriched ethanolamine plasmalogen improved learning and memory deficits by inhibiting neuronal apoptosis and enhancing the brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB)/cAMP response element-binding protein (CREB) signaling pathway in cultured cells and mice ( 50 , 51 ). Plasmalogens also accelerate hair growth and enhance the phosphorylation of AMP-activated protein kinase (AMPK) by stimulating the activity of transient receptor potential cation channel subfamily C member 4 in fibroblasts and hair follicles ( 52 ). These findings suggest a potential role of plasmalogens in regulating signaling pathways.…”

Asymmetric Distribution of Plasmalogens and Their Roles—A Mini Review

“…Recent studies addressing the potential function of plasmalogens in the activation of the cellular signaling pathway showed an activation of ERK- and AMP-activated protein kinase (AMPK) by exogenously added plasmalogens [ 92 , 93 ]. The physiological consequence of plasmalogen-mediated activation of the signaling pathway is not uncovered, although a beneficial effect on cognitive function is reported upon oral administration of plasmalogens [ 94 , 95 , 96 ].…”