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

Zeitler, Stefanie; Lian, Yong; Andreyeva, Aksana; Schumacher, Fabian; Monti, Juliana; Nürnberg, Bernd; Nowak, Gabriel; Kleuser, Burkhard; Reichel, Martin; Fejtová, Anna; Kornhuber, Johannes; Rhein, Cosima; Friedland, Kristina

doi:10.1111/jnc.14823

Cited by 12 publications

(15 citation statements)

References 63 publications

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“…Thus, both systems seem to be interconnected. Our earlier study in a neuronal cell line included data on FIASMA-mediated impaired TRPC6 function that was rescued by the application of bacterial sphingomyelinase [33]. Therefore, we thought ASM WT glial cells would be able to rescue the impaired TRPC6 function in ASM KO neurons with the secretion of ASM from WT glia to KO neurons.…”

Section: Discussionmentioning

confidence: 98%

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

Zeitler

Schumacher

Monti

et al. 2020

Cells

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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.

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Section: Discussionmentioning

confidence: 98%

“…Recently, we have demonstrated an interaction between ASM activity and TRPC6 function in rat pheochromocytoma 12 (PC12) cells. However, the link between TRPC6 and ASM remained correlative [33]. Therefore, in this study, we investigated the function of TRPC6 channels in neurons derived from ASM deficient mice (ASM KO) [34].…”

Section: Introductionmentioning

confidence: 99%

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

Zeitler

Schumacher

Monti

et al. 2020

Cells

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“…Vice versa, when sphinogomyelin hydrolysis was driven by treating hippocampal slices with neutral sphingomyelinase (NSM), Norman et al (2010) observed an increased excitability of CA1 pyramidal cells through a S1Pmediated mechanism. Finally, a recent study demonstrated that ASM modulates the biophysical properties of TRPC6 activity by controlling the interaction of TRPC6 channels with specific lipid subdomains (Zeitler et al, 2019). The apparent multitude of ion channels, whose gating characteristics as well as surface expression may be affected by S-ASM, may account for the different types of altered firing patterns in response to acute ASM inhibition that we observed in ARC39treated neurons (Figures 4, 5).…”

Section: Discussionmentioning

confidence: 65%

Tonic Control of Secretory Acid Sphingomyelinase Over Ventral Hippocampal Synaptic Transmission and Neuron Excitability

Lin

Kornhuber

Zheng

et al. 2021

Front. Cell. Neurosci.

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The acid sphingomyelinase (ASM) converts sphingomyelin into ceramide. Recent work has advanced the ASM/ceramide system as a major player in the pathogenesis of major depressive disorder (MDD). Indeed, ASM activity is enhanced in MDD patients and antidepressant drugs like fluoxetine act as functional inhibitors of ASM. Here, we employed the specific ASM inhibitor ARC39 to explore the acute effects of the enzyme on hippocampal synaptic transmission and cell excitability in adult mouse brain slice preparations. In both field potential and whole-cell recordings, ARC39 (1–3 μM) enhanced excitatory synaptic input onto ventral hippocampal CA1 pyramidal cells. The specificity of drug action was demonstrated by its lacking effect in slices from ASM knockout mice. In control condition, ARC39 strongly reduced firing in most CA1 pyramidal cells, together with membrane hyperpolarization. Such pronounced inhibitory action of ARC39 on soma excitability was largely reversed when GABAA receptors were blocked. The idea that ARC39 recruits GABAergic inhibition to dampen cell excitability was further reinforced by the drug’s ability to enhance the inhibitory synaptic drive onto pyramidal cells. In pyramidal cells that were pharmacologically isolated from synaptic input, the overall effect of ARC39 on cell firing was inhibitory, but some neurons displayed a biphasic response with a transient increase in firing, suggesting that ARC39 might alter intrinsic firing properties in a cell-specific fashion. Because ARC39 is charged at physiological pH and exerted all its effects within minutes of application, we propose that the neurophysiological actions reported here are due to the inhibition of secretory rather than lysosomal ASM. In summary, the ASM inhibitor ARC39 reveals a tonic control of the enzyme over ventral hippocampal excitability, which involves the intrinsic excitability of CA1 pyramidal cells as well as their excitatory and inhibitory synaptic inputs.

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“…These differential effects suggest that counterregulation of RNA levels restores Asm activity levels. Balanced Asm activity is essential for proper functioning of the cell [ 41 ], and it is possible that Smpd1 mRNA expression is upregulated as soon as cellular Asm activity decreases to a specific level to maintain optimal conditions. However, this regulatory effect was not evident in primary human blood cells; both 24 h and 48 h after fluoxetine stimulation, ASM activity and SMPD1 mRNA expression were reduced by approximately 80% as compared with control conditions.…”

Section: Discussionmentioning

confidence: 99%

mRNA Expression of SMPD1 Encoding Acid Sphingomyelinase Decreases upon Antidepressant Treatment

Rhein

Zoicas

Marx

et al. 2021

IJMS

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Major depressive disorder (MDD) is a severe psychiatric condition with key symptoms of low mood and lack of motivation, joy, and pleasure. Recently, the acid sphingomyelinase (ASM)/ceramide system has been implicated in the pathogenesis of MDD. ASM is a lysosomal glycoprotein that catalyzes the hydrolysis of sphingomyelin, an abundant component of membranes, into the bioactive sphingolipid ceramide, which impacts signaling pathways. ASM activity is inhibited by several common antidepressant drugs. Human and murine studies have confirmed that increased ASM activity and ceramide levels are correlated with MDD. To define a molecular marker for treatment monitoring, we investigated the mRNA expression of SMPD1, which encodes ASM, in primary cell culture models, a mouse study, and a human study with untreated MDD patients before and after antidepressive treatment. Our cell culture study showed that a common antidepressant inhibited ASM activity at the enzymatic level and also at the transcriptional level. In a genetically modified mouse line with depressive-like behavior, Smpd1 mRNA expression in dorsal hippocampal tissue was significantly decreased after treatment with a common antidepressant. The large human study showed that SMPD1 mRNA expression in untreated MDD patients decreased significantly after antidepressive treatment. This translational study shows that SMPD1 mRNA expression could serve as a molecular marker for treatment and adherence monitoring of MDD.

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

Cited by 12 publications

References 63 publications

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

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

Tonic Control of Secretory Acid Sphingomyelinase Over Ventral Hippocampal Synaptic Transmission and Neuron Excitability

mRNA Expression of SMPD1 Encoding Acid Sphingomyelinase Decreases upon Antidepressant Treatment

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