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

Zeitler S, Ye L, Andreyeva A, Schumacher F, Monti J, Nürnberg B, Nowak G, Kleuser B, Reichel M, Fejtová A, Kornhuber J, Rhein C, Friedland K (2019)

Publication Type: Journal article

Publication year: 2019

Journal

Journal of neurochemistry

DOI: 10.1111/jnc.14823

Abstract

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 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. (Figure presented.).

Authors with CRIS profile

Stefanie Zeitler Professur für Molekulare und Klinische Pharmazie Lian Ye Professur für Molekulare und Klinische Pharmazie Aksana Andreyeva Professur für Molekulare und Klinische Pharmazie Juliana Monti Lehrstuhl für Klinische Pharmakologie und Klinische Toxikologie Martin Reichel Department of Psychiatry and Psychotherapy Anna Fejtová Professur für Molekulare Psychiatrie Johannes Kornhuber Lehrstuhl für Psychiatrie und Psychotherapie Cosima Rhein Department of Psychiatry and Psychotherapy Kristina Friedland Professur für Molekulare und Klinische Pharmazie

Involved external institutions

Universität Potsdam DE Germany (DE) Universitätsklinikum Tübingen DE Germany (DE) Jagiellonian University / Uniwersytet Jagielloński (UJ) PL Poland (PL)

How to cite

APA:

Zeitler, S., Ye, L., Andreyeva, A., Schumacher, F., Monti, J., Nürnberg, B.,... Friedland, K. (2019). Acid sphingomyelinase – a regulator of canonical transient receptor potential channel 6 (TRPC6) activity. Journal of neurochemistry. https://dx.doi.org/10.1111/jnc.14823

MLA:

Zeitler, Stefanie, et al. "Acid sphingomyelinase – a regulator of canonical transient receptor potential channel 6 (TRPC6) activity." Journal of neurochemistry (2019).

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