Acid Sphingomyelinase Impacts Canonical Transient Receptor Potential Channels 6 (TRPC6) Activity in Primary Neuronal Systems

Zeitler S, Schumacher F, Monti J, Anni D, Guhathakurta D, Kleuser B, Friedland K, Fejtová A, Kornhuber J, Rhein C (2020)

Publication Type: Journal article

Publication year: 2020

Journal

Cells MDPI

Book Volume: 9

Journal Issue: 11

DOI: 10.3390/cells9112502

Abstract

: The acid sphingomyelinase (ASM)/ceramide system exhibits a crucial role in the pathology of major depressive disorder (MDD). ASM hydrolyzes the abundant membrane lipid sphingomyelin to ceramide that regulates the clustering of membrane proteins via microdomain and lipid raft organization. Several commonly used antidepressants, such as fluoxetine, rely on the functional inhibition of ASM in terms of their antidepressive pharmacological effects. Transient receptor potential canonical 6 (TRPC6) ion channels are located in the plasma membrane of neurons and serve as receptors for hyperforin, a phytochemical constituent of the antidepressive herbal remedy St. John's wort. TRPC6 channels are involved in the regulation of neuronal plasticity, which likely contributes to their antidepressant effect. In this work, we investigated the impact of reduced ASM activity on the TRPC6 function in neurons. A lipidomic analysis of cortical brain tissue of ASM deficient mice revealed a decrease in ceramide/sphingomyelin molar ratio and an increase in sphingosine. In neurons with ASM deletion, hyperforin-mediated Ca2+-influx via TRPC6 was decreased. Consequently, downstream activation of nuclear phospho-cAMP response element-binding protein (pCREB) was changed, a transcriptional factor involved in neuronal plasticity. Our study underlines the importance of balanced ASM activity, as well as sphingolipidome composition for optimal TRPC6 function. A better understanding of the interaction of the ASM/ceramide and TRPC6 systems could help to draw conclusions about the pathology of MDD.

Authors with CRIS profile

Juliana Monti Department of Psychiatry and Psychotherapy Daniela Anni Department of Psychiatry and Psychotherapy Debarpan Guhathakurta 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

Involved external institutions

Universität Potsdam DE Germany (DE) Freie Universität Berlin DE Germany (DE) Johannes Gutenberg-Universität Mainz (JGU) DE Germany (DE)

How to cite

APA:

Zeitler, S., Schumacher, F., Monti, J., Anni, D., Guhathakurta, D., Kleuser, B.,... Rhein, C. (2020). Acid Sphingomyelinase Impacts Canonical Transient Receptor Potential Channels 6 (TRPC6) Activity in Primary Neuronal Systems. Cells, 9(11). https://doi.org/10.3390/cells9112502

MLA:

Zeitler, Stefanie, et al. "Acid Sphingomyelinase Impacts Canonical Transient Receptor Potential Channels 6 (TRPC6) Activity in Primary Neuronal Systems." Cells 9.11 (2020).

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