Acid sphingomyelinase - a regulator of canonical transient receptor potential channel 6 (TRPC6) activity

  • Recent investigations propose the acid sphingomyelinase (ASM)/ceramide system as a novel target for antidepressant action. ASM catalyzes the breakdown of the abundant membrane lipid sphingomyelin to the lipid messenger ceramide. This ASM‐induced lipid modification induces a local shift in membrane properties, which influences receptor clustering and downstream signaling. Canonical transient receptor potential channels 6 (TRPC6) are non‐selective cation channels located in the cell membrane that play an important role in dendritic growth, synaptic plasticity and cognition in the brain. They can be activated by hyperforin, an ingredient of the herbal remedy St. John’s wort for treatment of depression disorders. Because of their role in the context of major depression, we investigated the crosstalk between the ASM/ceramide system and TRPC6 ion channels in a pheochromocytoma cell line 12 neuronal cell model (PC12 rat pheochromocytoma cell line). Ca2+ imaging experiments indicated that hyperforin‐induced Ca2+ influx through TRPC6 channelsRecent investigations propose the acid sphingomyelinase (ASM)/ceramide system as a novel target for antidepressant action. ASM catalyzes the breakdown of the abundant membrane lipid sphingomyelin to the lipid messenger ceramide. This ASM‐induced lipid modification induces a local shift in membrane properties, which influences receptor clustering and downstream signaling. Canonical transient receptor potential channels 6 (TRPC6) are non‐selective cation channels located in the cell membrane that play an important role in dendritic growth, synaptic plasticity and cognition in the brain. They can be activated by hyperforin, an ingredient of the herbal remedy St. John’s wort for treatment of depression disorders. Because of their role in the context of major depression, we investigated the crosstalk between the ASM/ceramide system and TRPC6 ion channels in a pheochromocytoma cell line 12 neuronal cell model (PC12 rat pheochromocytoma cell line). Ca2+ imaging experiments indicated that hyperforin‐induced Ca2+ influx through TRPC6 channels is modulated by ASM activity. While antidepressants, known as functional inhibitors of ASM activity, reduced TRPC6‐mediated Ca2+ influx, extracellular application of bacterial sphingomyelinase rebalanced TRPC6 activity in a concentration‐related way. This effect was confirmed in whole‐cell patch clamp electrophysiology recordings. Lipidomic analyses revealed a decrease in very long chain ceramide/sphingomyelin molar ratio after ASM inhibition, which was connected with changes in the abundance of TRPC6 channels in flotillin‐1–positive lipid rafts as visualized by western blotting. Our data provide evidence that the ASM/ceramide system regulates TRPC6 channels likely by controlling their recruitment to specific lipid subdomains and thereby fine‐tuning their physical properties.show moreshow less

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Author:Stefanie ZeitlerGND, Lian Ye, Aksana AndreyevaGND, Fabian SchumacherORCiDGND, Juliana Monti, Bernd NürnbergORCiDGND, Gabriel NowakORCiD, Burkhard KleuserORCiDGND, Martin ReichelORCiD, Anna FejtovaORCiD, Johannes KornhuberORCiDGND, Cosima RheinORCiD, Kristina FriedlandORCiDGND
DOI:https://doi.org/10.1111/jnc.14823
ISSN:0022-3042
ISSN:1471-4159
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=31310676
Parent Title (English):Journal of neurochemistry
Publisher:Wiley
Place of publication:Hoboken
Document Type:Article
Language:English
Date of first Publication:2019/07/16
Year of Completion:2019
Release Date:2020/11/20
Tag:TRPC6; acid sphingomyelinase; antidepressants; ceramide; hyperforin; lipid rafts
Volume:150
Issue:6
Page Number:13
First Page:678
Last Page:690
Funder:grant HYPZITRP [ERA-NET-Q7 Neuron/11/2014]; Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)German Research Foundation (DFG) [270949263/GRK2162, DFG/NU 53/12-2]
Organizational units:Mathematisch-Naturwissenschaftliche Fakultät / Institut für Biochemie und Biologie
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
Peer Review:Referiert